CN114599655A

CN114599655A - Imidazolidinone compound and preparation method and application thereof

Info

Publication number: CN114599655A
Application number: CN202080074622.2A
Authority: CN
Inventors: 祖厚贤; 宋西镇; 陈凯; 刘湘永; 陈洁; 边雅敬; 丁列明; 王家炳
Original assignee: Betta Pharmaceuticals Co Ltd
Current assignee: Betta Pharmaceuticals Co Ltd
Priority date: 2019-11-04
Filing date: 2020-11-04
Publication date: 2022-06-07
Anticipated expiration: 2040-11-04
Also published as: TW202132313A; AU2020379709A1; EP4056575A1; KR20220097466A; CA3156625A1; JP2023501324A; CN114599655B; US20230053342A1; CN118084935A; IL292592A; WO2021088839A1; EP4056575A4; MX2022005415A; BR112022008647A2

Abstract

Imidazolidinone compounds shown as a formula (I) or stereoisomers, geometric isomers or tautomers thereof, or pharmaceutically acceptable salts thereof, pharmaceutical compositions containing the compounds, a synthetic method and application of the compounds.

Description

Imidazolidinone compound and preparation method and application thereof

Technical Field

The present invention relates to imidazolidinone compounds which function by participating in the regulation of various processes such as cell proliferation, apoptosis, migration, and neovascularization. The invention also relates to a pharmaceutical composition containing the compounds and application of the compounds in treating PI3K mediated diseases.

Background

The PI3K signaling pathway is a key signaling pathway in cells that controls vital activities such as growth, proliferation, survival, differentiation, metastasis, and apoptosis. Since PI3K, Akt and mTOR are key sites on this pathway, it is called PI3K/Akt/mTOR signaling pathway. In recent years, PI3K inhibitor has become a hot point of research for anti-tumor drugs at home and abroad.

PI3K, when activated by RTK or Ras, catalyzes the production of phosphoinositide-3, 4-diphosphate (PIP2) to phosphoinositide-3, 4, 5-triphosphate (PIP 3). PIP3 binds to protein kinases such as Akt and 3-phosphoinositide (PIP) -dependent protein kinase (PDK), activates Akt by phosphorylating it, and transfers Akt from the cytoplasm into the nucleus. The activated Akt can further phosphorylate downstream effect substrates to influence Cell activities such as Cell survival, Cell cycle and growth (Ma K, Cheung SM, Marshall AJ and the like, Cell Signal,2008,20:684-694), so that the PI3K/Akt/mTOR Signal channel can inhibit apoptosis after being activated, enhance the tolerance of cells, promote the Cell survival and proliferation, participate in angiogenesis and promote the growth and metastasis of tumors.

Phosphatidylinositol 3-kinase (PI3K) belongs to the Lipid kinase (Lipid kinase) family, and the members of this family are classified into type I, type II and type III 3 (Vanhasebreck B, Waterfield MD; Exp Cell Res,1999,253:239-254) according to the difference in the activation mechanism and structural characteristics of PI 3K. Currently, type I PI3K is more well studied. Type I PI3K is further divided into two distinct subtypes IA and IB, which receive signaling signals from tyrosine protein kinase Receptors (RTKs) and G protein-coupled receptors (GPCRs), respectively (Wu P, Liu T, Hu Y; Curr Med Chem,2009,16:916-930), depending on the type of cell surface receptor. Class IA PI3K contains PI3K α, PI3K β and PI3K δ 3 subtypes, and class IB PI3K contains only PI3K γ one subtype. Type II PI3K kinase is divided into 3 subtypes of PI3KC2 alpha, PI3KC2 beta and PI3KC2 gamma according to the difference of C-terminal structures, but the substrate in vivo is not clear, and the understanding of the action mechanism and the specific function is relatively limited (Falasca M, T. Muffucci; Biochem Soc Trans,2007,35: 211-214). Type III PI3K kinase has only one member, Vps34(Vacuolar Protein locking 34), which functions at the Protein level to regulate the downstream mTOR signaling cascade (Schu P, Takegawa. K, Fry. M et al, Science,1993,260: 88-91).

Of the 4 subtypes of type I PI3K, PI 3K. alpha. and PI 3K. beta. are expressed in various organs, while PI 3K. delta. and PI 3K. gamma. are distributed mainly in bone marrow cells (Kong D, Yamori T; Cancer Sci,2008,99: 1734-. Among them, PI3K α has the closest relation with the occurrence and development of tumors, and the gene coding PI3K α catalytic subunit p110 α is PIK3CA, and its mutation is commonly found in various malignant tumors, including breast cancer, colon cancer, endometrial cancer, gastric cancer, ovarian cancer, lung cancer, etc. (Steelman. LS, Chappell. WH, Abrams. SL, etc., Aging,2011,3: 192-. Abnormal activation of PI3K α upregulates the activation of the PI3K signaling pathway, promoting cell hyperproliferation, growth and metastasis, leading to tumor formation. While the other three subtypes, PI3K β, PI3K δ and PI3K γ, play important roles in the process of tumor development by affecting catalytic activity, physicochemical properties, interactions and recognition, though playing roles in thrombosis, immune function, allergy and inflammatory response, respectively.

The PI3K inhibitor which is researched more in the early stage is wortmannin (wortmannin) and LY294002, and the two inhibitors play important roles in researching the physiological functions of PI3K, the action mechanism of a signal path and the like, provide important bases for subsequent researches, and are called as a first-generation PI3K inhibitor. Through the research on wortmannin and LY294002, a second-generation PI3K inhibitor with a newer structure, higher activity and better pharmacokinetic property is developed, and comprises morpholinyl, imidazopyridine, imidazoquinoline and the like, so that the second-generation PI3K inhibitor brings new hope for treating tumors. Among them, several dozen kinds of PI3K inhibitors are in clinical research stage, and mainly classified into pan PI3K inhibitors, PI3K/mTOR dual inhibitors, and PI3K subtype specific inhibitors.

Alpelisib (BYL719) is the first PI3K α selective inhibitor developed by Norvartis corporation, with an inhibitory activity against p110 α of 5 nM. Preclinical data show that BYL719 is able to inhibit phosphorylation of Akt, block PI3K signaling pathway and inhibit growth of breast Cancer cells containing PIK3CA mutations (Dejan Juric et al, Cancer Res,2012,72: 1). The compound has been approved by the Food and Drug Administration (FDA) to market 24/05/2019 for treating patients with HR having PIK3CA gene mutation⁺/HER2 ^-Postmenopausal female and male patients with advanced or metastatic breast cancer who undergo disease progression during or after endocrine treatment regimens. Meanwhile, the early results show that the PI3K alpha specific small molecule inhibitor is used for treating head and neck cancer, ovarian cancer and triple negative breast cancerCancer, HER2⁺Has better prospect in the treatment of diseases such as breast cancer, PIK3CA related overgrowth disease spectrum and the like. If the medicine can realize the expansion of indications, great economic and social benefits can be generated.

In order to achieve the purpose of better tumor treatment effect and better meet the market demand, a new drug selection is provided for clinical application, and a new generation of PI3K inhibitor with higher activity, better pharmacokinetics and lower toxicity is expected to be developed.

Disclosure of Invention

The invention aims to provide imidazolidinone compounds serving as PI3K inhibitors.

The invention firstly provides a compound shown in a formula (I) or a stereoisomer, a geometric isomer or a tautomer thereof, or a pharmaceutically acceptable salt, a solvate, a chelate, a non-covalent complex or a prodrug thereof,

wherein,

x is selected from O or S;

R ₁selected from H, CN, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-6Cycloalkyl radical, C_3-6Heterocyclic group, C_6-8Aryl radical, C_5-8Heteroaryl, OR_aor-NR_aR _b(ii) a Said C is_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-6Cycloalkyl radical, C_3-6Heterocycloalkyl radical, C_6-8Aryl and C_5-8Heteroaryl may optionally be substituted by 1 OR more groups selected from halogen, CN, OR_aOxo, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-6Cycloalkyl or C_3-6Substituted with a substituent of a heterocyclic group;

R ₂selected from H, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-6Cycloalkyl radical, C_3-6Heterocyclic group, C_6-8Aryl radical, C_5-8A heteroaryl group; said C is_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-6Cycloalkyl radical, C_3-6Heterocyclic group, C_6-8Aryl and C_5-8Heteroaryl groups may optionally be substituted by 1 or more groups selected from halogen, CN, -OH, -NO₂、C _1-6Alkyl radical, C_1-6Haloalkyl, C_2-6Alkenyl radical, C_2-6Haloalkenyl, C_2-6Alkynyl, C_2-6Halogenated alkynyl, C_3-6Cycloalkyl radical, C_3-6Halogenocycloalkyl, C_3-6Heterocyclic group, C_3-6Halogenated heterocyclic group, C_6-8Aryl radical, C_6-8Halogenated aryl, C_5-8Heteroaryl group, C_5-8Haloheteroaryl, oxo, -OR_a、-NR _aR _b、-C(O)R _a、-C(O)OR _a、-C(O)NR _aR _b、-S(O)R _aor-S (O)₂R _aSubstituted with the substituent(s);

R ₃selected from H, halogen, CN, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, -OR_aor-NR_aR _b(ii) a Said C is_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl may optionally be substituted by 1 OR more groups selected from halogen, CN, -OR_a、-NR _aR _b、-C(O)R _a、-C(O)OR _a、-C(O)NR _aR _b、-S(O)R _aor-S (O)₂R _aSubstituted with a substituent of (a);

R ₄selected from H, halogen, CN, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, oxo, C_1-6Haloalkyl, C_2-6Haloalkenyl, C_2-6Halogenated alkynyl, C_1-6Alkoxy radical, C_1-6Haloalkoxy, -OR_a、-NR _aR _b、-C(O)R _a、-C(O)OR _a、-C(O)NR _aR _b、-S(O)R _aor-S (O)₂R _a；

R ₅Selected from H, halogen, CN, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Haloalkyl, C_2-6Haloalkenyl, C_2-6Halogenated alkynyl, C_1-6Alkoxy radical, C_1-6Haloalkoxy, -OR_a、-NR _aR _b、-S(O)R _aor-S (O)₂R _a；

R ₆Selected from H, halogen, CN, oxo, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Alkoxy radical, C_3-6Cycloalkyl radical, C_3-6Heterocyclic group, C_6-8Aryl radical, C_5-8Heteroaryl, -OR_a、-NR _aR _b、-C(O)R _a、-C(O)OR _a、-C(O)NR _aR _b、-S(O)R _aor-S (O)₂R _a(ii) a Said C is_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Alkoxy radical, C_3-6Cycloalkyl radical, C_3-6Heterocyclic group, C_6-8Aryl and C_5-8Heteroaryl may optionally be substituted by 1 or more groups selected from halogen, CN, oxo, -NO₂、C _1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, -OR_a、-NR _aR _b、-C(O)R _a、-C(O)OR _a、-C(O)NR _aR _b、-S(O)R _aor-S (O)₂R _aSubstituted with a group of (a); or,

two R₆Together with the C atom to which they are attached form C_3-6Cycloalkyl or C_3-6A heterocyclic group;

R _aand R_bEach independently selected from H, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Alkoxy radical, C_3-6Cycloalkyl radical, C_3-6Heterocyclic group, C_6-8Aryl radical, C_5-8A heteroaryl group; said C is_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Alkoxy radical, C_3-6Cycloalkyl radical, C_3-6Heterocyclic group, C_6-8Aryl radical, C_5-8Heteroaryl being optionally substituted by halogen, CN, -OH, -NH₂、C _1-6Alkyl radical, C_1-6Alkoxy radical, C_1-6Haloalkyl, C_1-6Haloalkoxy;

m is selected from 0, 1,2, 3 or 4;

n is selected from 0, 1,2 or 3;

y is selected from 0, 1,2, 3,4,5 or 6.

The present invention further provides preferred embodiments of compounds of formula (i) or stereoisomers, geometric isomers or tautomers thereof:

in some embodiments, R₁Is C_1-6Alkyl or C_3-6Cycloalkyl radical, said C_1-6Alkyl and C_3-6Cycloalkyl groups may independently be optionally substituted with halogen.

In some embodiments, R₂Selected from H, C_1-6Alkyl radical, C _3-6Cycloalkyl radical, C_3-6Heterocyclic group, C_6-8Aryl or C_5-8A heteroaryl group; said C is_1-6Alkyl radical, C_3-6Cycloalkyl radical, C_3-6Heterocyclic group, C_6-8Aryl and C_5-8Heteroaryl can be optionally substituted with 1 or more halogens, -CN, -OH, -NR_aR _b、C _1-6Alkyl or C_1-6Haloalkyl; the R is_aAnd R_bEach independently selected from H or C_1-6An alkyl group.

In some embodiments, R₃Selected from H, halogen, CN, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Haloalkyl, C_2-6Haloalkenyl or C_2-6A haloalkynyl group.

In some embodiments, R₆Selected from H, halogen, CN, -NH₂Oxo, -OH, C_1-6Alkyl radical, C_2- ₆Alkenyl radical, C_2-6Alkynyl, C_1-6Alkoxy radical, C_1-6Haloalkyl, C_2-6Haloalkenyl, C_2-6Halogenated alkynyl, C_3-6Cycloalkyl radical, C_3-6Heterocyclic group, C_6-8Aryl or C_5-8A heteroaryl group.

In some embodiments, the compound of formula (I) is further a compound of formula (II):

in some embodiments, the compound of formula (I) is further a compound of formula (III-1):

wherein, R is₁Is C_1-6Alkyl or C_1-6A haloalkyl group.

In some embodiments, the compound of formula (I) is further a compound of formula (III-2):

in some embodiments, R₃Selected from H, halogen, C_1-6Alkyl or C_2-6An alkenyl group.

In some embodiments, R₄And R₅Are all H.

In some embodiments, the compound of formula (I) is further a compound of formula (IV):

wherein:

R ₁is C_1-6Alkyl or C_1-6A haloalkyl group;

R ₂selected from H, C_1-6Alkyl radical, C_3-6Cycloalkyl radical, C_3-6Heterocyclic group, C_6-8Aryl or C_5-8A heteroaryl group; said C is_1-6Alkyl radical, C_3-6Cycloalkyl radical, C_3-6Heterocyclic group, C_6-8Aryl and C_5-8Heteroaryl can be optionally substituted by 1 or more halogens, -CN, -OH, -NR_aR _b、C _1-6Alkyl radical, C_1-6Haloalkyl, C_1-6Alkoxy or C_1-6Haloalkoxy;

R ₃selected from H, halogen, C_1-6Alkyl or C_2-6An alkenyl group;

R ₆selected from H, halogen, -NH₂Oxo, -OH, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_1-6Haloalkyl, C_1-6Haloalkoxy, C_3-6Cycloalkyl or C_6-8An aryl group;

R _aand R_bEach independently selected from H or C_1-6An alkyl group;

y is selected from 0, 1,2, 3,4,5 or 6.

In some embodiments, X is O.

In some embodiments, the compound of formula (i) is further a compound of formula (v):

in some embodiments, R₂Selected from H, C_1-6Alkyl radical, C_3-6Cycloalkyl radical, C_3-6Heterocyclic group, C₆Aryl or C_5-6A heteroaryl group; said C is_1-6Alkyl radical, C_3-6Cycloalkyl radical, C_3-6Heterocyclic group, C₆Aryl and C_5-6Heteroaryl may optionally be substituted by 1 or more halogens, -CN, -OH, -N- (CH)₃) ₂、C _1-6Alkyl or C_1-6Haloalkyl.

In some embodiments, R₆Selected from H, halogen, -NH₂Oxo, -OH, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_3-6CycloalkanesRadical or C₆And (4) an aryl group.

In some embodiments, the compound of formula (I) is further a compound of formula (VI):

wherein,

R ₁is selected from C_1-6Alkyl or C_1-6A haloalkyl group;

R ₂selected from H, C_1-6Alkyl radical, C_3-6Cycloalkyl radical, C_3-6Heterocyclic group, C₆Aryl or C_5-6A heteroaryl group; said C is_1-6Alkyl radical, C_3-6Cycloalkyl radical, C_3-6Heterocyclic group, C₆Aryl and C_5-6Heteroaryl may optionally be substituted by 1 or more halogens, -CN, -OH, -N- (CH)₃) ₂、C _1-6Alkyl or C_1-6Haloalkyl.

In some embodiments, R₁Is C_1-4An alkyl group; r₂Selected from H, C_1-6Alkyl radical, C_3-6Cycloalkyl radical, C_3-6Heterocyclic group, C₆Aryl or C₅-C ₆A heteroaryl group; the R is₁And R₂May independently be optionally substituted with halogen.

In some embodiments, R₂Is selected from C_1-6Alkyl radical, C_1-6Haloalkyl, C_3-6Cycloalkyl radical, C_3-6Halocycloalkyl, phenyl or halophenyl.

In some embodiments, R₁Is selected from-CH (CH)₃) ₂、-C(CH ₃) ₃、-CF ₃or-CHF₂。

In some embodiments, the compound of formula (I) is further represented by formula (VII):

wherein, R is₂Selected from H, C_1-6Alkyl radical, C_3-6Cycloalkyl radical, C_3-6Heterocyclic group, C₆Aryl or C_5-6A heteroaryl group; the R is₂Optionally substituted with halogen.

In some embodiments, R₁Is C_1-4An alkyl group; r₂Selected from H, C_1-6Alkyl radical, C_3-6Cycloalkyl radical, C_3-6Heterocyclic group, C₆Aryl or C_5-6A heteroaryl group; the R is₁And R₂May independently be optionally substituted by F.

In some embodiments, R₂Is selected from-CH₃、-CH ₂CH ₃、-CH(CH ₃) ₂、-CH ₂CF ₃Cyclopropyl, cyclobutyl, phenyl or pyridyl; the-CH₃、-CH ₂CH ₃、-CH(CH ₃) ₂、-CH ₂CF ₃Cyclopropyl, cyclobutyl, phenyl or pyridyl optionally substituted by halogen.

In some embodiments, the halogen is F.

In some embodiments, R₂Is selected from-CH₃、-CH(CH ₃) ₂Cyclopropyl, phenyl or halogen substituted phenyl.

In some embodiments, R₁is-CH (CH)₃) ₂。

In some embodiments, R₁is-CHF₂。

In some embodiments, R₂Is selected from-CH₃、-CH(CH ₃) ₂Cyclopropyl, phenyl or F substituted phenyl, pyridyl or F substituted pyridyl.

In some embodiments, R₂Is selected from-CH₃、-CH(CH ₃) ₂Cyclopropyl, phenyl or F-substituted phenyl.

In some embodiments, R₂is-CH (CH)₃) ₂Or a cyclopropyl group.

In some embodiments, the compound of formula (I) is further represented by formula (VIII):

the present invention further provides certain particularly preferred embodiments of compounds of formula (i), or stereoisomers, geometric isomers or tautomers thereof, wherein:

1) (2S) -1- (2- (5-isopropyl-3-methyl-2, 4-dioxoimidazolidin-1-yl) -5, 6-dihydrobenzo [ f]Imidazo [1,2-d][1,4]Oxazazem

-9-yl) pyrrolidine-2-carboxamide;

2) (2S) -1- (2- (3-cyclopropyl-5-isopropyl-2, 4-dioxoimidazolidin-1-yl) -5, 6-dihydrobenzo [ f]Imidazole [1,2-d ]][1,4]Oxazazem

-9-yl) pyrrolidine-2-carboxamide;

3) (2S) -1- (2- (5-isopropyl-2, 4-dioxo-3- (2,2, 2-trifluoroethyl) imidazolidin-1-yl) -5, 6-dihydrobenzo [ f]Imidazole [1,2-d ]][1,4]Oxazazem

-9-yl) pyrrolidine-2-carboxamide;

4) (2S) -1- (2- (3- (4-fluorophenyl) -5-isopropyl-2, 4-dioxoimidazolidin-1-yl) -5, 6-dihydrobenzo [ f]Imidazo [1,2-d ] s][1,4]Oxazazem

-9-yl) pyrrolidine-2-carboxamide;

5) (2S) -1- (2- (5-cyclopropyl-3-methyl-2, 4-dioxoimidazolidin-1-yl) -5, 6-dihydrobenzo [ f]Imidazo [1,2-d ] s][1,4]Oxazazem

-9-yl) pyrrolidine-2-carboxamide;

6) (2S) -1- (2- (3-cyclobutyl-5-isopropyl-2, 4-dioxoimidazolidin-1-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1,2-d ] s][1,4]Oxazazem

-9-yl) pyrrolidine-2-carboxamide;

7) (2S) -1- (2- (3-Ethyl-5-isopropyl-2, 4-dioxoimidazolidin-1-yl) -5, 6-dihydrobenzo [ f]Imidazo [1,2-d ] s][1,4]Oxazazem

-9-yl) pyrrolidine-2-carboxamide;

8) (2S) -1- (2- (5-difluoromethyl-3-methyl-2, 4-dioxoimidazolidin-1-yl) -5, 6-dihydrobenzo [ f]Imidazo [1,2-d ] s][1,4]Oxazazem

-9-yl) pyrrolidine-2-carboxamide;

9) (2S) -1- (2- (5-isopropyl) group-2, 4-dioxo-3-phenylimidazolidin-1-yl) -5, 6-dihydrobenzo [ f]Imidazo [1,2-d ] s][1,4]Oxazazem

-9-yl) pyrrolidine-2-carboxamide;

10) (S) -1- (2- ((S) -5-isopropyl-2, 4-dioxo-3-phenylimidazolidin-1-yl) -5, 6-dihydrobenzo [ f]Imidazo [1,2-d ] s][1,4]Oxazazem

-9-yl) pyrrolidine-2-carboxamide;

11) (S) -1- (2- ((R) -5-isopropyl-2, 4-dioxo-3-phenylimidazolidin-1-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1,2-d ] s][1,4]Oxazazem

-9-yl) pyrrolidine-2-carboxamide;

12) (2S) -1- (2- (5-isopropyl-2, 4-dioxo-3- (4- (trifluoromethyl) phenyl) imidazolidin-1-yl) -5, 6-dihydrobenzo [ f]Imidazole [1,2-d ]][1,4]Oxazazem

-9-yl) pyrrolidine-2-carboxamide;

13) (2S) -1- (2- (5-isopropyl-2, 4-dioxo-3-propylimidazolidin-1-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1,2-d ] s][1,4]Oxazazem

-9-yl) pyrrolidine-2-carboxamide;

14) (2S) -1- (2- (3-cyclopropyl-5-isopropyl) -2, 4-dioxoimidazolidin-1-yl) -5, 6-dihydrobenzo [ f]Imidazo [1,2-d ] s][1,4]Oxazazem

-9-yl) -2-methylpyrrolidine-2-carboxamide;

15) (2S) -1- (2- (3-cyclopropyl-5-isopropyl) -2, 4-dioxoimidazolidin-1-yl) -5, 6-dihydrobenzo [ f ] imidazo [1,2-d ] [1,4] thiazolin-9-yl) -4, 4-difluoropyrrolidine-2-carboxamide;

16) (2S) -1- (2- (5-isopropyl-3- (1-methyl-1H-1, 2, 4-triazol-5-yl) -2, 4-dioxoimidazolidin-1-yl) -5, 6-dihydrobenzo [ f]Imidazo [1,2-d ] s][1,4]Oxazazem

-9-yl) pyrrolidine-2-carboxamide;

17) (2S,4S) -4-amino-1- (2- (3-cyclopropyl-5-isopropyl-2, 4-dioxo-imidazolidin-1-yl) -5, 6-dihydrobenzo [ f)]Imidazole [1,2-d ]][1,4]Oxazazem

-9-yl) pyrrolidine-2-carboxamide;

18) (2S) -1- (2- (3- (2-fluorophenyl) -5-isopropyl-2, 4-dioxoimidazolidin-1-yl) -5, 6-dihydrobenzo [ f]Imidazole [1,2-d ]][1,4]Oxazazepine

-9-yl) pyrrolidine-2-carboxamide;

19) (2S) -1- (2- (3- (4-chlorophenyl) -5-isopropyl-2, 4-dioxoimidazolidin-1-yl) -5, 6-dihydrobenzo [ f]Imidazo [1,2-d ] s][1,4]Oxazazepine

-9-yl) pyrrolidine-2-carboxamide;

20) (2S) -4- (tert-butoxy) -1- (2- (3-cyclopropyl-5-isopropyl-2, 4-dioxoimidazolidin-1-yl) -5, 6-dihydrobenzo [ f]Imidazole [1,2 ]]-d][1,4]Oxazazem

-9-yl) pyrrolidine-2-carboxamide;

21) (2S) -1- (2- (3-cyclopropyl-5-isopropyl) -2, 4-dioxoimidazolidin-1-yl) -5, 6-dihydrobenzo [ f]Imidazo [1,2-d ] s][1,4]Oxazazem

-9-yl) -4, 4-dimethylpyrrolidine-2-carboxamide;

22) (2S) -1- (2- (3- (2, 2-difluoroethyl) -5-isopropyl-2, 4-dioxoimidazolidin-1-yl) -5, 6-dihydrobenzo [ f]Imidazo [1,2-d ] s][1,4]Oxazazem

-9-yl) pyrrolidine-2-carboxamide;

23) (2S) -1- (2- (3, 5-diisopropyl-2, 4-dioxoimidazolidin-1-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1,2-d ] s][1,4]Oxazazem

-9-yl) pyrrolidine-2-carboxamide;

24) (2S) -1- (2- (3-cyclopropyl-5-isopropyl) -2, 4-dioxoimidazolidin-1-yl) -5, 6-dihydrobenzo [ f]Imidazo [1,2-d ] s][1,4]Oxazazem

-9-yl) -4-phenylpyrrolidine-2-carboxamide;

25) (2S) -1- (2- (3- (3-chloro-5-cyanophenyl) -5-isopropyl-2, 4-dioxoimidazolidin-1-yl) -5, 6-dihydrobenzo [ f ] imidazo [1,2-d ] [1,4] thiazolin-9-yl) pyrrolidine-2-carboxamide;

26) (2S) -1- (2- (3, 5-diisopropyl-2, 4-dioxoimidazolidin-1-yl) -5, 6-dihydrobenzo [ f ] imidazo [1,2-d ] [1,4] thiazolin-9-yl) pyrrolidine-2-carboxamide;

27) (2S) -1- (2- (3-azetidin-3-yl) -5-isopropyl-2, 4-dioxoimidazolidin-1-yl) -5, 6-dihydrobenzo [ f]Imidazo [1,2-d ] s][1,4]Oxazazem

-9-yl) pyrrolidine-2-carboxamide;

28) (2S) -1- (2- (3-methyl-2, 4-dioxoimidazolidin-1-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1,2-d ] s][1,4]Oxazazem

-9-yl) pyrrolidine-2-carboxamide;

29) (2S) -1- (2- (5-tert-butyl-3-methyl-2, 4-dioxoimidazolidin-1-yl) -5, 6-dihydrobenzo [ f]Imidazo [1,2-d ] s][1,4]Oxazazem

-9-yl) pyrrolidine-2-carboxamide;

30) (S) -1- (2- ((R) -3- (4-fluorophenyl) -5-isopropyl-2, 4-dioxoimidazolidin-1-yl) -5, 6-dihydrobenzo [ f]Imidazo [1,2 ] s]-d][1,4]Oxazazem

-9-yl) pyrrolidine-2-carboxamide;

31) (S) -1- (2- ((S) -3- (4-fluorophenyl) -5-isopropyl-2, 4-dioxo-imidazolidin-1-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1,2 ] s]-d][1,4]Oxazazem

-9-yl) pyrrolidine-2-carboxamide;

32) (2S) -1- (2- ((5R) -3-cyclopropyl-5-isopropyl-2, 4-dioxoimidazolidin-1-yl) -5, 6-dihydrobenzo [ f]Imidazo [1,2-d ] s][1,4]Oxazazem

-9-yl) pyrrolidine-2-carboxamide;

33) (2S) -1- (2- ((5S) -3-cyclopropyl-5-isopropyl-2, 4-dioxoimidazolidin-1-yl) -5, 6-dihydrobenzo [ f]Imidazo [1,2-d ] s][1,4]Oxazazem

-9-yl) pyrrolidine-2-carboxamide;

34) (2S) -1- (2- (3- (2-hydroxyethyl) -5-isopropyl-2, 4-dioxoimidazolidin-1-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1,2-d ] s][1,4]Oxazazem

-9-yl) pyrrolidine-2-carboxamide;

35) (2S) -1- (2- (3- (2-fluoroethyl) -5-isopropyl-2, 4-dioxoimidazolidin-1-yl) -5, 6-dihydrobenzo [ f]Imidazo [1,2-d][1,4]Oxazazem

-9-yl) pyrrolidine-2-carboxamide;

36) (2S) -1- (2- (3- (2- (dimethylamino) ethyl) -5-) isopropyl-2, 4-dioxoimidazolidin-1-yl) -5, 6-dihydrobenzo [ f]Imidazo [1,2-d ] s][1,4]Oxazazem

-9-yl) pyrrolidine-2-carboxamide;

37) (2S) -1- (2- (3-cyclopropyl-5-isopropyl) -2, 4-dioxoimidazolidin-1-yl) -5, 6-dihydrobenzo [ f ] imidazo [1,2-d ] [1,4] thiazolin-9-yl) pyrrolidine-2-carboxamide;

38) (2S) -1- (2- (3- (6-Fluoropyridin-3-Yl) -5-isopropyl-2, 4-dioxoimidazolidin-1-Yl) -5, 6-Dihydrobenzo [ f]Imidazo [1,2-d ] s][1,4]Oxazazem

-9-yl) pyrrolidine-2-carboxamide;

39) (2S) -1- (2- (3- (5-Fluoropyridin-3-Yl) -5-isopropyl-2, 4-dioxoimidazolidin-1-Yl) -5, 6-Dihydrobenzo [ f]Imidazo [1,2 ] s]-d][1,4]Oxazazem

-9-yl) pyrrolidine-2-carboxamide;

40) (2S) -1- (2- (3- (3-cyano-5-fluorophenyl) -5-isopropyl-2, 4-dioxoimidazolidin-1-yl) -5, 6-dihydrobenzo [ f]Imidazo [1,2-d ] s][1,4]Oxazazem

-9-yl) -4-fluoropyrrolidine-2-carboxamide;

41) (2S) -1- (2- (3- (3-Chloropyrimidin-2-yl) -5-isopropyl-2, 4-dioxoimidazolidin-1-yl) -5, 6-dihydrobenzo [ f]Imidazo [1,2-d ] s][1,4]Oxazazem

-9-yl) pyrrolidine-2-carboxamide;

42) (2S) -1- (2- (3-cyclopentyl-5-isopropyl-2, 4-dioxoimidazolidin-1-yl) -5, 6-dihydrobenzo [ f]Imidazole [1,2-d ]][1,4]Oxazazem

-9-yl) pyrrolidine-2-carboxamide;

43) (2S) -1- (2- (3- (cyanomethyl) -5-isopropyl-2, 4-dioxoimidazolidin-1-yl) -5, 6-dihydrobenzo [ f]Imidazo [1,2-d ] s][1,4]Oxazazem

-9-yl) pyrrolidine-2-carboxylic acid esterAn amide;

44) (2S) -1- (2- (5-isopropyl-3-methyl-2, 4-dioxoimidazolidin-1-yl) -5, 6-dihydrobenzo [ f ] imidazo [1,2-d ] [1,4] thiazolin-9-yl) pyrrolidine-2-carboxamide;

45) (2S) -1- (2- (3- (2, 2-difluoroethyl) -5-isopropyl-2, 4-dioxoimidazolidin-1-yl) -5, 6-dihydrobenzo [ f ] imidazo [1,2-d ] [1,4] thiazolin-9-yl) pyrrolidine-2-carboxamide;

46) (2S) -1- (2- (3-cyclopropyl-5-isopropyl-2, 4-dioxoimidazolidin-1-yl) -3-vinyl-5, 6-dihydrobenzo [ f)]Imidazo [1,2-d ] s][1,4]Oxazazem

-9-yl) pyrrolidine-2-carboxamide;

47) (2S) -1- (3-chloro-2- (3-cyclopropyl-5-isopropyl-2, 4-dioxoimidazolidin-1-yl) -5, 6-dihydrobenzo [ f]Imidazo [1,2-d ] s][1,4]Oxazazem

-9-yl) pyrrolidine-2-carboxamide;

48) (2S) -1- (2- (3-cyclopropyl-5- (difluoromethyl) -2, 4-dioxoimidazolidin-1-yl) -5, 6-dihydrobenzo [ f ] imidazo [1,2-d ] [1,4] thiazolin-9-yl) pyrrolidine-2-carboxamide;

49) (2S,3S) -1- (2- (3-cyclopropyl-5-isopropyl-2, 4-dioxoimidazolidin-1-yl) -5, 6-dihydrobenzo [ f]Imidazo [1,2-d ] s][1,4]Oxazazem

-9-yl) -3-hydroxypyrrolidine-2-carboxamide;

50) (2S) -1- (2- (3-cyclopropyl-5-isopropyl-2, 4-dioxoimidazolidin-1-yl) -3-methyl-5, 6-dihydrobenzo [ f]Imidazo [1,2-d ] s][1,4]Oxazazem

-9-yl) -4-oxopyrrolidine-2-carboxamide;

51) (2S) -4-cyclohexyl-1- (2- (3-cyclopropyl-5-isopropyl-2, 4-dioxoimidazolidin-1-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1,2-d ] s][1,4]Oxazazem

-9-yl) pyrrolidine-2-carboxamide;

52) (2S) -1- (2- (3-cyclopropyl-5-isopropyl-2, 4-dioxoimidazolidin-1-yl) -5, 6-dihydrobenzo [ f ] imidazo [1,2-d ] [1,4] thiazolin-9-yl) -5-oxopyrrolidine-2-carboxamide.

The invention also provides a pharmaceutical composition, which comprises at least one compound shown in the formula (I) of the invention with a therapeutically effective amount and at least one pharmaceutically acceptable auxiliary material.

The invention further provides a pharmaceutical composition, wherein the weight ratio of the compound shown in the formula (I) to the auxiliary materials in the pharmaceutical composition is 0.0001-10.

The invention provides the use of a compound of formula (I) or a pharmaceutical composition comprising a compound of formula (I) in the manufacture of a medicament.

The invention further provides a preferable technical scheme of the application:

preferably, the medicament is for treating, preventing, delaying or preventing the occurrence or progression of cancer or cancer metastasis.

Preferably, the medicament is for the treatment of cancer.

Preferably, the medicament is for use as a PI3K inhibitor.

Preferably, the medicament is for the treatment of a PI 3K-mediated disease.

Preferably, the PI3K includes PI3K α, PI3K β, PI3K δ, and/or PI3K γ.

Preferably, the PI3K is PI3K α.

Preferably, the PI 3K-mediated disease is cancer.

Preferably, the cancer is selected from sarcoma, prostate cancer, breast cancer, pancreatic cancer, gastrointestinal cancer, colorectal cancer, thyroid cancer, liver cancer, adrenal cancer, glioma, endometrial cancer, melanoma, kidney cancer, bladder cancer, uterine cancer, vaginal cancer, ovarian cancer, multiple myeloma, esophageal cancer, leukemia, brain cancer, oral and pharyngeal cancer, throat cancer, lymphoma, basal cell carcinoma, polycythemia vera, essential thrombocytosis.

The invention also provides a method of treating and/or preventing a subject having a PI 3K-mediated disease by administering to a subject in need thereof a therapeutically effective amount of at least any one compound of formula (i) or a pharmaceutical composition comprising a compound of formula (i).

Preferably, in the above method, the PI3K includes PI3K α, PI3K β, PI3K δ, and/or PI3K γ.

Preferably, in the above method, the PI3K is PI3K α.

Preferably, in the above method, the PI 3K-mediated disease is cancer.

Preferably, in the above method, the cancer is sarcoma, prostate cancer, breast cancer, pancreatic cancer, gastrointestinal cancer, colorectal cancer, thyroid cancer, liver cancer, adrenal cancer, glioma, endometrial cancer, melanoma, kidney cancer, bladder cancer, uterine cancer, vaginal cancer, ovarian cancer, multiple myeloma, esophageal cancer, leukemia, brain cancer, oral and pharyngeal cancer, laryngeal cancer, lymphoma, basal cell carcinoma, polycythemia vera, essential thrombocytosis.

The invention also provides a method of treating cancer, such as sarcoma, prostate cancer, breast cancer, pancreatic cancer, gastrointestinal cancer, colorectal cancer, thyroid cancer, liver cancer, adrenal cancer, glioma, endometrial cancer, melanoma, kidney cancer, bladder cancer, uterine cancer, vaginal cancer, ovarian cancer, multiple myeloma, esophageal cancer, leukemia, brain cancer, oral and pharyngeal cancer, laryngeal cancer, lymphoma, basal cell carcinoma, polycythemia vera, primary thrombocythemia, by administering to a subject a therapeutically effective amount of at least one compound of formula (i), or a pharmaceutical composition containing a compound of formula (i).

Preferably, in the above method, the subject is a human.

The invention relates to compounds which are inhibitors of PI3K, and the use of these compounds for the manufacture of a medicament for the treatment or prevention of diseases mediated by PI3K in vivo. The compound has the characteristics of good treatment effect, high selectivity and high bioavailability as an active ingredient. The compound is used as a medicine to be on the market, has the characteristics of low cost and convenient taking, is more beneficial to the wide application of the medicines, and can more effectively help patients to overcome pains and improve the life quality.

The terms used in the present invention have the following meanings:

in the present invention, unless otherwise specified, the term "alkyl" includes straight-chain, branched-chain or cyclic saturated alkyl groups. For example, alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclobutyl, cyclopentyl, and cyclohexyl. Similarly, C_1-4"C" in alkyl_1-4"refers to a group containing 1,2, 3, or 4 carbon atoms arranged in a linear, branched, or cyclic fashion.

"cycloalkyl" refers to a cyclic saturated monovalent hydrocarbon radical. Similarly, C_3-6"C" in cycloalkyl_3-6"refers to a saturated monovalent hydrocarbon radical containing 3,4,5, or 6 carbon atoms arranged in a cyclic fashion. Representative cycloalkyl groups include, but are not limited to, cyclopropane, cyclobutane, cyclopentane, or cyclohexane and the like.

In the present invention, unless otherwise indicated, the term "heterocyclyl" refers to a substituted or unsubstituted non-aromatic 3 to 6 membered monocyclic system consisting of C atoms and 1 to 3 heteroatoms selected from N, O or S, and wherein the N or S heteroatoms are optionally oxidized and the N heteroatoms may optionally be quaternized. The heterocycloalkyl group can be attached to any heteroatom or carbon atom that results in a stable structure. Representative heterocyclyl groups include, but are not limited to, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxopiperazinyl, oxopiperidinyl, oxoazepinyl, azepinyl, tetrahydrofuranyl, dioxolanyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydrooxazolyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, and oxadiazolyl.

"halogen" means fluorine (F), chlorine (Cl), bromine (Br) or iodine (I). Preferred halogen groups are fluorine, chlorine and bromine.

"halo" refers to fluoro, chloro, bromo, or iodo groups.

"substituted" means that one or more hydrogen atoms in a group are each replaced by the same or different substituent. Representative substituents include, but are not limited to, halogen, amino, hydroxy, cyano, alkyl, alkenyl, alkynyl, cycloalkyl, haloalkyl, alkoxy, aryl, haloaryl, arylalkyl, arylalkenyl, heterocyclyl, cycloalkoxy, alkylamino.

In the present invention, unless otherwise indicated, the term "aryl" refers to a substituted or unsubstituted monocyclic or polycyclic ring system containing carbon atoms. A preferred aryl group is phenyl.

In the context of the present invention, unless otherwise indicated, the term "heteroaryl" refers to an unsubstituted or substituted stable 5-or 6-membered monoaromatic ring system or an unsubstituted or substituted 9-or 10-membered benzo-fused heteroaromatic ring system or bis-heteroaromatic ring system consisting of carbon atoms and from 1 to 4 heteroatoms selected from the group consisting of N, O or S, where the N or S heteroatoms may optionally be oxidized and the N heteroatoms may optionally be quaternized. The heteroaryl group may be attached to any heteroatom or carbon atom that results in a stable structure. Examples of heteroaryl groups include, but are not limited to, thienyl, furyl, imidazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thiadiazolyl, triazolyl, pyridyl, pyridazinyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, benzofuranyl, benzothienyl, benzisoxazolyl, benzoxazolyl, benzopyrazolyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl, adenine, quinolinyl, or isoquinolinyl.

The "compounds" of the present invention include compounds of formula (I), and all pharmaceutically acceptable forms thereof. These pharmaceutically acceptable forms include salts, solvates, non-covalent complexes, chelates, stereoisomers (including diastereomers, enantiomers, and racemates), geometric isomers, isotopically labeled compounds, tautomers, prodrugs, or any mixtures of all of the foregoing.

The "enantiomers" are a pair of stereoisomers that are non-superimposable on each other and that are mirror images of each other, and the 1:1 mixture of a pair of enantiomers is a "racemic" mixture. When specifying the stereochemistry of the compounds of the present invention, conventional RS systems (e.g., (1S,2S) are used to specify a single stereoisomer with known relative and absolute configurations of two chiral centers).

The "diastereomers" are stereoisomers having at least two asymmetric atoms, but which are not mirror images of each other. When the compound is a pure enantiomer, the stereochemistry at each chiral carbon may be specified by R or S.

Resolved compounds with unknown absolute configuration may be named (+) or (-) depending on the direction (dextro-or levorotatory) in which they rotate plane-polarized light at the wavelength of the sodium D line. Alternatively, the resolved compounds may be defined by the respective retention times of the respective enantiomers/diastereomers by chiral HPLC.

One skilled in the art will recognize that the compounds of the present invention contain chiral centers and thus may exist in different isomeric forms. Unless otherwise indicated, the compounds of the present invention are intended to include all such possible isomers, including racemic mixtures, optically pure forms, and mixtures of isomers in any proportion. For example, compounds of formula (VIII) include the compound of example 2, the compound of example 32, the compound of example 33, and mixtures of example 32 and example 33 in any ratio. Optically active (R) -and (S) -isomers can be prepared using optically active starting material syntheses or chiral reagents, or resolved using conventional techniques (e.g., separation on chiral SFC or HPLC columns).

The term "pharmaceutically acceptable" refers to those known for use in animals, particularly humans.

The term "composition" as used herein includes a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from the specified ingredients in the specified amounts. Accordingly, pharmaceutical compositions comprising the compounds of the present invention as an active ingredient and processes for preparing the compounds are all aspects of the present invention. Furthermore, some of the crystalline forms of the compounds may exist as polymorphic forms, which are also included in the present invention. In addition, some compounds form solvates with water (e.g., hydrates) or common organic solvents, and such solvates are also encompassed by the present invention.

By "therapeutically effective amount" is meant an amount of a compound that, when administered to a subject for treatment, treats and prevents and/or inhibits at least one clinical symptom of a disease, condition, symptom, indication, and/or disorder, sufficient to effect treatment of the disease, condition, symptom, indication, or disorder. The specific "therapeutically effective amount" may vary depending on the compound, the route of administration, the age of the patient, the weight of the patient, the type, symptoms, and severity of the disease or disorder being treated, and the like. An appropriate dosage, where possible, will be readily apparent to those skilled in the art and may be determined by routine experimentation.

The compounds provided by the present invention may also exist in the form of "pharmaceutically acceptable salts". In terms of pharmaceutical applications, the salts of the compounds provided by the present invention are non-toxic pharmaceutically acceptable salts. Pharmaceutically acceptable salt forms include pharmaceutically acceptable acid/anion or base/cation salts. The pharmaceutically acceptable acid/anion salts are typically present in the protonated form of a basic nitrogen with an inorganic or organic acid. Typical organic or inorganic acids include, but are not limited to, hydrochloric, hydrobromic, hydroiodic, perchloric, sulfuric, nitric, phosphoric, acetic, propionic, glycolic, lactic, succinic, maleic, fumaric, malic, tartaric, citric, benzoic, mandelic, methanesulfonic, isethionic, benzenesulfonic, oxalic, pamoic, 2-naphthalenesulfonic, p-toluenesulfonic, cyclohexylamine sulfonic, salicylic, saccharinic or trifluoroacetic acids. Pharmaceutically acceptable base/cation salts include, but are not limited to, aluminum, calcium, chloroprocaine, choline, diethanolamine, ethylenediamine, lithium, magnesium, potassium, sodium, and zinc salts.

"prodrugs" of the compounds of the invention are included within the scope of the invention. In general, such "prodrugs" are functional derivatives that are readily converted in vivo to the desired compound. Thus, the term "administering" with respect to the treatment provided herein includes administering a compound disclosed herein, or, although not specifically disclosed, is capable of being converted in vivo upon administration to a subject to treat the various disorders described herein. Conventional methods for selecting and preparing suitable prodrug derivatives are described, for example, in the Design of Prodrugs (Design of produgs, ed.h. bundgaard, Elsevier, 1985).

It will be apparent that the definition of any substituent or variable at a particular position in one molecule is independent of the definition of any substituent or variable at a particular position in other molecules. It will be readily appreciated that the compounds of the present invention may be prepared by selecting appropriate substituents or substitution patterns according to the state of the art to provide chemically stable and readily preparable syntheses using the state of the art or methods described herein.

When the compounds of formula (I) and pharmaceutically acceptable salts thereof are in the form of solvates or polymorphs, the present invention includes any possible solvates and polymorphs. The type of the solvent forming the solvate is not particularly limited as long as the solvent is pharmacologically acceptable. For example, water, ethanol, propanol, acetone, and the like can be used.

The term "pharmaceutically acceptable salt" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids. When the compound provided by the present invention is an acid, its corresponding salt can be prepared from pharmaceutically acceptable non-toxic bases including inorganic bases and organic bases. Salts derived from inorganic bases include salts of aluminum, ammonium, calcium, copper, iron, ferrous, lithium, magnesium, manganese, potassium, sodium, zinc and the like. In particular, ammonium, calcium, magnesium, potassium and sodium salts are preferred. Non-toxic organic bases which can be derivatized to form pharmaceutically acceptable salts include primary, secondary and tertiary amines, as well as cyclic amines and substituted amines, such as naturally occurring and synthetic substituted amines. Other pharmaceutically acceptable non-toxic organic bases capable of forming salts include ion exchange resins and arginine, betaine, caffeine, choline, N' -dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, reduced glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like.

When the compound provided by the present invention is a base, its corresponding salt can be prepared from pharmaceutically acceptable non-toxic acids including inorganic acids and organic acids. Such acids include, for example, acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, formic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, isethionic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucic acid, nitric acid, pamoic acid, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, tartaric acid, p-toluenesulfonic acid and the like. Preferably, citric, hydrobromic, formic, hydrochloric, maleic, phosphoric, sulfuric and tartaric acids. More preferably formic acid and hydrochloric acid. Since the compounds of formula (I) are to be used as medicaments, it is preferred to use them in substantially pure form, for example, at least 60% pure, more suitably at least 75% pure, especially suitably at least 98% pure (% by weight).

The pharmaceutical composition provided by the invention comprises a compound shown as a formula (I) (or pharmaceutically acceptable salt thereof) as an active component, a pharmaceutically acceptable excipient and other optional therapeutic components or auxiliary materials. Although the most suitable mode of administration of the active ingredient in any given case will depend on the particular host, host nature and severity of the condition being treated, the pharmaceutical compositions of the present invention include those suitable for oral, rectal, topical and parenteral (including subcutaneous, intramuscular, intravenous) administration. The pharmaceutical compositions of the present invention may be conveniently prepared in unit dosage forms well known in the art and by any of the methods of preparation well known in the pharmaceutical arts.

In practice, the compounds of formula (I), or prodrugs, or metabolites, or pharmaceutically acceptable salts thereof, of the present invention may be incorporated as the active ingredient in combination with pharmaceutical carriers for the preparation of pharmaceutical compositions according to conventional pharmaceutical compounding techniques. The pharmaceutical carrier may take a wide variety of forms depending on the intended mode of administration, e.g., oral or parenteral (including intravenous). Thus, the pharmaceutical compositions of the present invention may take the form of discrete units suitable for oral administration, such as capsules, cachets or tablets containing a predetermined dose of the active ingredient. Further, the pharmaceutical composition of the present invention may take the form of a powder, granules, a solution, an aqueous suspension, a non-aqueous liquid, an oil-in-water emulsion, or a water-in-oil emulsion. Alternatively, in addition to the usual dosage forms mentioned above, the compound of formula (I) or a pharmaceutically acceptable salt thereof may be administered by controlled release means and/or delivery devices. The pharmaceutical composition of the present invention can be prepared by any pharmaceutical method. In general, such methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more of the necessary ingredients. In general, the pharmaceutical compositions are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or a mixture of both. In addition, the product can be conveniently prepared to a desired appearance.

Accordingly, the pharmaceutical composition of the present invention comprises a pharmaceutically acceptable carrier and a compound represented by formula (i), or a pharmaceutically acceptable salt thereof. The compounds of formula (I), or pharmaceutically acceptable salts thereof, are also included in the pharmaceutical compositions of the present invention, along with one or more other compounds which are therapeutically active in combination.

The pharmaceutical carrier employed in the present invention may be, for example, a solid carrier, a liquid carrier or a gaseous carrier. Examples of solid carriers include lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid. Examples of liquid carriers include syrup, peanut oil, olive oil, and water. Examples of gas carriers; including carbon dioxide and nitrogen. Any convenient pharmaceutical medium may be employed in the preparation of the pharmaceutical oral formulations. For example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like can be used in oral liquid preparations such as suspensions, elixirs and solutions; and carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents and the like may be used in solid preparations for oral administration such as powders, capsules and tablets. In view of ease of administration, tablets and capsules are the first choice for oral formulations. Alternatively, tablet coatings may use standard aqueous or non-aqueous formulation techniques.

Tablets containing a compound or pharmaceutical composition of the invention may be prepared by, optionally, compressing or molding with one or more accessory ingredients or adjuvants. The active ingredient may be mixed in a free-flowing form such as a powder or granules with lubricants, inert diluents, surface active or dispersing agents and the compressed tablets may be prepared by compression in a suitable machine. Molded tablets may be made by wetting a powdered compound or pharmaceutical composition with an inert liquid diluent and then shaping in a suitable machine. Preferably, each tablet contains about 0.05mg to 5g of active ingredient, and each sachet or capsule contains about 0.05mg to 5g of active ingredient. For example, a dosage form intended for oral administration to humans comprises from about 0.5mg to about 5g of the active ingredient, in combination with suitable and conveniently metered amounts of auxiliary materials which constitute from about 5% to about 95% of the total weight of the pharmaceutical composition. Unit dosage forms generally contain from about 1mg to about 2g of active ingredient, typically 25mg, 50mg, 100mg, 200mg, 300mg, 400mg, 500mg, 600mg, 800mg or 1000 mg.

The pharmaceutical compositions provided by the present invention, which are suitable for parenteral administration, can be prepared as aqueous solutions or suspensions by adding the active ingredient to water. A suitable surfactant such as hydroxypropyl cellulose may be included. Dispersions may also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils. Further, preservatives may also be included in the pharmaceutical compositions of the present invention to prevent the growth of harmful microorganisms.

The present invention provides pharmaceutical compositions, including sterile aqueous solutions or dispersions, suitable for injectable use. Further, the above pharmaceutical composition may be prepared in the form of sterile powders for the extemporaneous preparation of sterile injectable solutions. In any event, the final injection form must be sterile and must be readily flowable for ease of injection. Furthermore, the pharmaceutical composition must be stable during preparation and storage. Therefore, preservation against contamination by microorganisms such as bacteria and fungi is preferred. The carrier can be a solvent or dispersion medium, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol, liquid polyethylene glycol), vegetable oil, and suitable mixtures thereof.

The pharmaceutical compositions provided herein may be in a form suitable for topical administration, for example, as an aerosol, cream, ointment, lotion, dusting powder, or other similar dosage form. Further, the pharmaceutical compositions provided herein may take a form suitable for use in a transdermal delivery device. These formulations can be prepared by conventional processing methods using the compounds of formula (I) of the present invention, or pharmaceutically acceptable salts thereof. As an example, creams or ointments are prepared by adding hydrophilic materials and water (both in a total amount of about 5 wt% to 10 wt% of the compound) to the above-mentioned compounds to make creams or ointments with desired consistency.

The pharmaceutical composition provided by the invention can be prepared into a form which takes a solid as a carrier and is suitable for rectal administration. The mixture is formed into unit dose suppositories which are the most preferred dosage forms. Suitable excipients include cocoa butter and other materials commonly used in the art. Suppositories can be conveniently prepared by first mixing the pharmaceutical composition with the softened or melted excipients, then cooling and moulding.

In addition to the aforementioned carrier components, the aforementioned pharmaceutical preparations may also include, as appropriate, one or more additional adjuvant components, such as diluents, buffers, flavoring agents, binders, surfactants, thickeners, lubricants, preservatives (including antioxidants), and the like. Further, other adjuvants may also include penetration enhancers to regulate the osmolarity of the drug with blood. Pharmaceutical compositions comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, may also be prepared in the form of a powder or a concentrate.

Detailed Description

The preparation of the compounds of formula (I) according to the invention is further illustrated, but not limited, by the following examples.

The following examples are intended only to illustrate specific embodiments of the present invention so as to enable those skilled in the art to understand the present invention, but not to limit the scope of the present invention. In the embodiments of the present invention, technical means or methods not specifically described are conventional in the art. All parts and percentages herein are by weight and all temperatures are in degrees Celsius, unless otherwise indicated.

The following abbreviations are used in the examples:

DCM: methylene dichloride

DMF: n, N-dimethylformamide

DIEA: n, N-diisopropylethylamine

PE: petroleum ether

EA: acetic acid ethyl ester

NIS: n-iodosuccinimide

LCMS or LC-MS: liquid chromatography-mass spectrometry

THF: tetrahydrofuran (THF)

DMSO (dimethylsulfoxide): dimethyl sulfoxide

Et ₃N or TEA: triethylamine

HATU: 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate

Hex: n-hexane

h. hr or hrs: hour(s)

LiHMDS: lithium bis (trimethylsilyl) amide

[PdCl ₂(dppf)]CH ₂Cl ₂: [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride dichloromethane complex

Boc: boc-butoxy group

min: minute(s) of

RT or RT: and (4) room temperature.

General route:

the compounds of formula (VI) may be prepared by the following route:

preparation of intermediate M-5:

step 1: synthesis of Compound M-2

A1000 mL single vial was charged with 4-bromo-2-hydroxybenzaldehyde (40g) and MeOH (400mL), stirred in an ice bath with dropwise addition of aqueous ammonia (136.50g), and heated in a 35 ℃ oil bath for reaction. And monitoring by LC-MS (liquid chromatography-mass spectrometry) until the reaction is finished, concentrating the reaction solution, adding water for dilution, extracting for four times by using EA, combining organic phases, drying, concentrating, purifying by column chromatography (PE: EA is 3:1), and concentrating to obtain 34.55g of a compound M-2.

LC-MS[M+H ⁺]：239。

Step 2: synthesis of Compound M-3

A1000 mL single-neck bottle was charged with Compound M-2(34.55g), Cs₂CO ₃(133g) And DMF (300mL) is stirred at normal temperature for 20min, then 1, 2-dibromoethane (54.30g) is added dropwise, after the dropwise addition is finished, the mixture is placed into an oil bath at 80 ℃ for reflux reaction, and LC-MS monitors until the reaction is complete. The reaction solution was concentrated, diluted with water, extracted three times with EA, the organic phases were combined, dried, concentrated under reduced pressure, purified by column chromatography (PE: EA 70:30), and concentrated to obtain 21.37g of compound M-3.

LC-MS[M+H ⁺]：265。

1H NMR (500MHz, chloroform-d) δ 8.38(d, J ═ 8.5Hz,1H),7.30-7.15(m,3H),6.99(s,1H),4.47-4.43(m,2H),4.41-4.35(m, 2H).

And step 3: synthesis of Compound M-4

Adding a compound M-3(21.37g) and DMF (100mL) into a 1000mL single-neck bottle, stirring for dissolving, dropwise adding a solution of NIS (50.78g) dissolved in DMF (100mL), placing into a 60 ℃ oil bath for reacting overnight after dropwise adding, monitoring by LC-MS until the reaction is finished, adding water into the reaction solution, precipitating a solid, filtering by suction, and drying to obtain 35g of a compound M-4.

LC-MS[M+H ⁺]：517。

1H NMR(500MHz,Chloroform-d)δ8.30(d,J＝8.6Hz,1H),7.25-7.16(m,2H),4.46-4.41(m,2H),4.36-4.32(m,2H)。

And 4, step 4: synthesis of Compound M-5

To a 500mL three-necked flask, compound M-4(35g) and THF (150mL) were added under nitrogen, and 100mL of ethylmagnesium bromide (1M solution in THF) was added dropwise to the reaction system at-40 ℃ and the reaction was stirred at-40 ℃. And monitoring by LC-MS (liquid chromatography-mass spectrometry) until the reaction is completed, adding a saturated ammonium chloride solution under an ice bath condition to quench the reaction, adding EA (ethylene-acetic acid) to extract for three times, combining organic phases, drying, concentrating, adding methyl tert-butyl ether, pulping, performing suction filtration, and drying to obtain 19.8g of a compound M-5.

LC-MS[M+H ⁺]：391。

1H NMR(500MHz,DMSO-d6)δ8.22(d,J＝8.6Hz,1H),7.55(s,1H),7.31-7.23(m,2H),4.47-4.39(m,4H)。

Example 1(2S) -1- (2- (5-isopropyl-3-methyl-2, 4-dioxoimidazolidin-1-yl) -5, 6-dihydrobenzo [ f]Imidazo [1,2-d ] s][1,4]Oxazazem

Synthesis of (E) -9-yl) pyrrolidine-2-carboxamide (Compound 1)

Step 1: synthesis of Compounds 1-3

To a 500mL three-necked flask were added compound 1-1(9g), compound 1-2(16.8g), DCM (200mL) and HATU (31.25g), and TEA (50.21g) was added dropwise under ice-bath conditions, followed by reaction at room temperature. Monitoring by LC-MS until the reaction is finished, adding waterQuenching, separating organic phase, washing organic phase with water, and removing anhydrous Na₂SO ₄Drying, concentration and purification by column chromatography (PE: EA 50:50) gave 9.2g of compounds 1-3.

LC-MS[M-Boc+H] ⁺：131。

Step 2: synthesis of Compounds 1-4

To a solution of compound 1-3(1.3g) in dichloromethane (10mL) was added HCl/dioxane solution (10mL, 4.0mol/L) and stirred at room temperature for 3 hours. After the reaction was completed, 0.9g of the compound 1-4 was obtained by concentration. The compound was used in the next reaction without further purification.

LC-MS[M+H] ⁺：131。

And 3, step 3: synthesis of Compounds 1-5

Compounds 1-4(900mg) and TEA (4.19g) were dissolved in THF (50 mL). Under an ice-water bath, a solution of triphosgene (802mg) in THF (10mL) was slowly added dropwise to the reaction system, and the reaction was stirred for 12 hours while naturally warming to room temperature. And (3) monitoring by LCMS, adding 5mL of water to quench the reaction after the reaction is finished, concentrating, and adding dichloromethane/water for extraction and liquid separation. Anhydrous Na for organic phase₂SO ₄Drying, concentrating, and purifying by column chromatography (PE: EA: 1) to obtain 732mg of compound 1-5.

LC-MS[M+H] ⁺：157。

And 4, step 4: synthesis of Compounds 1-6

Compounds No. 1-5(177mg), Compound M-5(443mg), CuI (64.75mg), trans-N, N' -dimethylcyclohexane-1, 2-diamine (48.36mg) and K₃PO ₄(721.68mg) was dissolved in DMF (5mL), and the mixture was purged with nitrogen three times, and the temperature was raised to 110 ℃ to react for 2 hours. After LCMS monitoring till the reaction is finished, adding EA (100mL) to dilute the reaction solution, washing the reaction solution with water, combining organic phases, and using anhydrous Na as an organic phase₂SO ₄Drying, concentrating, and purifying by column chromatography (PE: EA 70:30) to obtain 350mg of compound 1-6.

LC-MS[M+H] ⁺：419。

And 5: synthesis of Compounds 1-7

Add Compounds 1-6 (350) to a 100mL single-necked flaskmg), L-proline (290mg), K₃PO ₄(848mg), CuI (79.8mg) and DMSO (5mL) under nitrogen, stirring the reaction at 120 ℃ for 3 h. After LCMS monitoring reaction was complete, the reaction was filtered, the filter cake was washed with DMSO (3mL), and the filtrate was used directly in the next step.

LC-MS[M+H] ⁺：454。

Step 6: synthesis of Compound 1

DCM (12mL), NH was added to the filtrate from step 5 under a nitrogen blanket₄Cl (445mg) and DIEA (2.17g) were cooled to 0 ℃ and HATU (1.27g) was added to the reaction system under ice-cooling, and the reaction was stirred at 0 ℃ for 20 min. After LCMS monitoring the reaction, DCM was added to dilute the reaction, water was washed and the organic phase was Na anhydrous₂SO ₄Drying, concentrating, and purifying the crude product by column chromatography (PE: EA 100:0-0:100) to obtain 300mg of compound 1.

LC-MS[M+H] ⁺：453。

¹H NMR(500MHz,DMSO-d6)δ8.04(d,J＝8.9Hz,1H),7.41(s,1H),7.24(s,1H),7.05(s,1H),6.32(d,J＝8.7Hz,1H),6.03(s,1H),4.62-4.51(m,1H),4.45-4.30(m,4H),3.94(d,J＝8.7Hz,1H),3.55(t,J＝7.3Hz,1H),3.23(q,J＝7.2Hz,1H),2.92(s,3H),2.68(m,1H),2.26-2.12(m,1H),1.96(m,3H),1.16(d,J＝7.0Hz,3H),0.74(d,J＝6.8Hz,3H)。

Example 2(2S) -1- (2- (3-cyclopropyl-5-isopropyl-2, 4-dioxoimidazolidin-1-yl) -5, 6-dihydrobenzo [ f)]Imidazole [1,2-d ]][1,4]Oxazazem

Synthesis of (E) -9-yl) pyrrolidine-2-carboxamide (Compound 2)

Step 1: synthesis of Compound 2-2

To a 250mL one-neck flask were added compound 1-1(5.0g), DCM (100mL) and HATU (9.55g), under nitrogen, TEA (8.15g) and compound 2-1(1.45g) under ice-bath conditions, and reacted at room temperature for 2 h. After the reaction was completed by LCMS, the reaction mixture was concentrated, diluted with EA, washed with water, dried over anhydrous sodium sulfate, and concentrated to obtain 5.0g of Compound 2-2, which was used in the next step.

LC-MS[M-Boc+H] ⁺：157。

¹H NMR(500MHz,DMSO-d6)δ7.91(s,1H),6.54(d,J＝9.0Hz,1H),3.69-3.58(m,1H),2.65-2.55(m,1H),1.88-1.80(m,1H),1.37(s,9H),0.79(d,J＝6.0Hz,6H),0.62-0.58(m,2H),0.42-0.30(m,2H)。

Step 2: synthesis of Compounds 2-3

To a 250mL one-neck flask, compound 2-2(5g), DCM (20mL) and HCl/dioxane (20mL, 4.0mol/L) were added and reacted at room temperature for 2 h. After completion of the reaction, the reaction solution was concentrated by LCMS to obtain 3.75g of Compound 2-3.

LC-MS[M+H] ⁺：157。

And step 3: synthesis of Compounds 2-4

Adding the compound 2-3(2.0g), DCM (50mL) and TEA (4.20g) into a 250mL three-necked bottle under the protection of nitrogen, dropwise adding a solution of triphosgene (1.54g) dissolved in DCM (50mL) into the reaction system under the ice bath condition, stirring the reaction for 2 hours under the ice bath condition, monitoring the reaction by LCMS, quenching the reaction by ice water under the ice bath condition, concentrating the reaction solution, extracting by EA, and extracting by anhydrous Na₂SO ₄Drying, concentrating, and purifying the crude product by column chromatography (PE: EA: 100:0-50:50) to obtain 810mg of compound 2-4.

LC-MS[M+H] ⁺：183/185。

¹H NMR (500MHz, chloroform-d) δ 6.28(s,1H),3.85(d, J ═ 3.6Hz,1H),2.66-2.48(m, J ═ 3.7Hz,1H),2.25-2.15(m,1H),1.03(d, J ═ 6.5Hz,3H),0.98-0.91(m,4H),0.88(d, J ═ 7.0Hz, 3H).

And 4, step 4: synthesis of Compounds 2 to 5

To a 50mL single-necked flask, Compound 2-4(431mg), Compound M-5(700mg), DMF (10mL), CuI (102mg), trans-N, N' -dimethylcyclohexane-1, 2-diamine (77mg), and K were added₃PO ₄(760mg), under nitrogen, the temperature was raised to 120 ℃ and the reaction was stirred for 2 hours. After the reaction was completed by LCMS, EA was diluted, washed with water and anhydrous Na₂SO ₄Drying, concentrating, and purifying by column chromatography (PE: EA: 100:0-60:40) to obtain 642mg of compound 2-5.

LC-MS[M+H] ⁺：445/447。

¹H NMR (500MHz, chloroform-d) δ 8.23(d, J ═ 8.5Hz,1H),7.27(s,1H),7.22(d, J ═ 8.7Hz,1H),7.20(s,1H),4.63-4.59(m,1H),4.51-4.38(m,2H),4.36(t, J ═ 4.3Hz,2H),2.79-2.71(m,1H),2.68-2.60(m,1H),1.24(d, J ═ 7.1Hz,3H),1.02-0.94(m,4H),0.81(d, J ═ 6.9Hz, 3H).

And 5: synthesis of Compounds 2-6

To a 30mL microwave tube was added compound 2-5(642mg), compound M-12(415mg), K₃PO ₄(919mg) and DMSO (10mL), nitrogen purge, to which CuI (83mg) was added, and microwave reaction was carried out at 120 ℃ for 1 h. After completion of the reaction, LCMS monitored the reaction solution directly for next step.

LC-MS[M+H] ⁺：480。

Step 6: synthesis of Compound 2

The reaction mixture obtained in step 5 was charged into a 50mL single-neck flask, purged with nitrogen, and DCM (10mL) and NH were added₄Cl (462mg) and TEA (1.46g), the reaction was cooled to 0 ℃ and HATU (3.28g) was added under ice-cooling, and the reaction was stirred at 0 ℃ for 1 h. After the reaction was completed by LCMS, DCM was added to dilute the reaction solution, water was washed, and the organic phase was Na anhydrous₂SO ₄Drying, concentrating, and purifying the crude product by Pre-HPLC (C18 column, H)₂O MeOH ═ 95:5-50:50), yielding 85mg of compound 2.

LC-MS[M+H] ⁺：479。

¹H NMR(500MHz,DMSO-d6)δ8.03(d,J＝9.0Hz,1H),7.40(s,1H),7.24(s,1H),7.05(s,1H),6.32(d,J＝8.9Hz,1H),6.03(d,J＝2.6Hz,1H),4.48(s,1H),4.41-4.29(m,4H),3.94(d,J＝8.8Hz,1H),3.55(t,J＝8.1Hz,1H),3.25-3.19(m,1H),2.74-2.55(m,2H),2.25-2.14(m,1H),2.07-1.85(m,3H),1.13(d,J＝7.0Hz,3H),0.88(d,J＝7.2Hz,2H),0.81(d,J＝3.9Hz,2H),0.71(d,J＝6.8Hz,3H)。

And 7: preparation of Compound 32 and Compound 33

In this embodiment, compound 2 is resolved on a chiral column under the following conditions, whereby compound 32 (pre-peak) and compound 33 (post-peak) can be obtained.

Chiral HPLC conditions:

compound 32: LC-MS [ M + H ]] ⁺：479。

¹H NMR(500MHz,DMSO-d6)δ8.03(d,J＝9.0Hz,1H),7.40(s,1H),7.24(s,1H),7.05(s,1H),6.32(d,J＝8.9Hz,1H),6.03(d,J＝2.6Hz,1H),4.48(s,1H),4.41–4.29(m,4H),3.94(d,J＝8.8Hz,1H),3.55(t,J＝8.1Hz,1H),3.25-3.19(m,1H),2.74–2.55(m,2H),2.25-2.14(m,1H),2.07-1.85(m,3H),1.13(d,J＝7.0Hz,3H),0.88(d,J＝7.2Hz,2H),0.81(d,J＝3.9Hz,2H),0.71(d,J＝6.8Hz,3H).

Compound 33: LC-MS [ M + H ]] ⁺：479。

Example 3(2S) -1- (2- (5-isopropyl-2, 4-dioxo-3- (2,2, 2-trifluoroethyl) imidazolidin-1-yl) -5, 6-dihydrobenzo [ f]Imidazole [1,2-d ]][1,4]Oxazazem

Synthesis of (E) -9-yl) pyrrolidine-2-carboxamide (Compound 3)

Step 1: synthesis of Compound 3-2

Compound 3-0(2g) and compound 3-1(583mg) were added to DCM (100ml), and HATU (2.67g) and DIEA (2.28g) were successively added to the reaction system, and the reaction was stirred at room temperature for 12 hours. Water was added to the reaction solution, followed by liquid separation and concentration to obtain a residue. To the residue was added ethyl acetate (25mL), washed with water, saturated brine and the organic phase was washed with anhydrous Na₂SO ₄Drying and concentrating to obtain 1.8g of product.

LC-MS[M+H] ⁺：421。

Step 2: synthesis of Compound 3-3

Diethylamine (10mL) was added to a solution of compound 3-2(1.8g) in DCM (10mL) and stirred at RT for 2 h. Concentration under reduced pressure gave a residue, which was purified by column chromatography to give 0.70g of Compound 3-3.

LC-MS[M+H] ⁺：199。

And step 3: synthesis of Compounds 3-4

To a 50mL three-necked flask was added compound 3-3(200mg), CH₃CN(10mL)，NaHCO ₃(254mg) was purged with nitrogen three times, and p-nitrophenyl chloroformate (203mg) was added thereto, and the reaction was stirred at room temperature for 2 hours. Then, 6mL of water was added to the reaction system, and the reaction was stirred at room temperature for 3 hours. After the reaction, concentrating under reduced pressure to obtain a residue, adding EA to the residue for dilution, washing the organic phase with water, a potassium carbonate aqueous solution and saturated sodium chloride water successively, drying the organic phase with anhydrous sodium sulfate, and concentrating to obtain a crude product. The crude product was purified by column chromatography (PE: EA 60:40) to give 195mg of compound 3-4.

LC-MS[M+H] ⁺：225。

And 4, step 4: synthesis of Compounds 3-5

Mixing Compound 3-4(138mg), Compound M-5(200mg), CuI (39mg), trans-N, N' -dimethylcyclohexane-1, 2-diamine (29mg), K₃PO ₄(326mg) was dissolved in DMF (5mL), and the mixture was replaced with nitrogen three times, and the reaction was warmed to 110 ℃ for 2 hours. After completion of the reaction, EA was added to the reaction mixture to dilute, washed once with water, washed three times with saturated brine, and the organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (PE: EA ═ 100:0-70:30) to obtain 180mg of compound 3-5.

LC-MS[M+H ⁺]：487/489。

And 5: synthesis of Compounds 3-6

To a 50mL single-necked flask was added compound 3-5(117mg), compound M-12(138mg), K₃PO ₄(356mg), CuI (46mg) and DMSO (3mL) were purged with nitrogen three times, warmed to 120 ℃ and stirred for 3 hours. After completion of the reaction, the reaction solution was filtered, the filter cake was washed with DMSO (3mL), and the filtrate was used directly in the next step.

LC-MS[M+H] ⁺：522。

Step 6: synthesis of Compound 3

DCM (6mL), NH was added to the filtrate from step 5 under a nitrogen blanket₄Cl (127mg), DIEA (613mg), and the reaction mixture was cooled to 0 ℃ and HATU (447mg) was added thereto in portions under ice-cooling, and the reaction was stirred at 0 ℃ for 20 min. After the reaction, dichloromethane is added to dilute the reaction solution, the reaction solution is washed with water and saturated salt solution, the organic phase is dried by anhydrous sodium sulfate, and the crude product is obtained by decompression and concentration. The resulting crude product was purified by Pre-HPLC to give 85mg of Compound 3.

LC-MS[M+H] ⁺：521。

1H NMR(500MHz,DMSO-d6)δ8.05(d,J＝8.5Hz,1H),7.41(s,1H),7.29(s,1H),7.06(s,1H),6.33(d,J＝9Hz,1H),6.04(s,1H),4.71–4.70(m,1H),4.38–4.24(m,6H),3.95(d,J＝8.5Hz,1H),3.55(t,J＝7.3Hz,1H),3.28-3.20(m,1H),2.70(brs,1H),2.25-2.15(m,1H),2.00–1.94(m,3H),1.17(d,J＝7.0Hz,3H),0.75(d,J＝7Hz,3H)。

Example 4(2S) -1- (2- (3- (4-fluorophenyl) -5-isopropyl-2, 4-dioxoimidazolidin-1-yl) -5, 6-dihydrobenzo [ f]Imidazo [1,2-d ] s][1,4]Oxazazem

Synthesis of (E) -9-yl) pyrrolidine-2-carboxamide (Compound 4)

Step 1: synthesis of Compound 4-1

To a solution of compound 1-1(1.5g) and p-fluoroaniline (921mg) in DCM (50ml) were added HATU (3.39g) and DIEA (2.68 g). The reaction was stirred at room temperature for 12 h. After the reaction is finished, adding water into the reaction solution for dilution, separating liquid, and sequentially using 1N HCl and NaHCO for an organic phase₃Washing with saturated aqueous solution and saturated brine, and removing anhydrous Na from organic phase₂SO ₄Drying and concentrating to obtain a crude product. The crude product was purified by column chromatography (EA/PE ═ 0-30%) to give 2.1g of compound 4-1.

LC-MS[M-Boc+H] ⁺：211。

Step 2: synthesis of Compound 4-2

Compound 4-1(2.1g) was added to a solution of HCl/dioxane (10mL, 4M) and stirred at room temperature for 12 h. Concentration under reduced pressure gave 1.64g of Compound 4-2, which was used in the next reaction without further purification.

LC-MS[M+H] ⁺：211。

And step 3: synthesis of Compound 4-3

To a 50mL three-necked flask was added compound 4-2(500mg), CH₃CN(30mL)，NaHCO ₃(681mg) was purged with nitrogen three times, and then p-nitrophenyl chloroformate (449mg) was added thereto, and the reaction was stirred at room temperature for 2 hours. To the reaction solution, 18mL of water was added, and the reaction was stirred at room temperature for 3 hours.

After completion of the reaction, the reaction mixture was concentrated under reduced pressure to give a residue, which was diluted with ethyl acetate (100mL) and the organic phase was washed with water (50mL) and 5% K₂CO ₃The aqueous solution (50mL) was washed with saturated brine, separated, and the organic phase was dried over anhydrous sodium sulfate and concentrated to give the crude product. Subjecting the crude product to column chromatography (EA/PE 0-40%)Purification gave 447mg of compound 4-3.

LC-MS[M+H] ⁺：237。

And 4, step 4: synthesis of Compound 4-4

Mixing Compound 4-3(144mg), Compound M-5(200mg), CuI (39mg), trans-N, N' -dimethylcyclohexane-1, 2-diamine (29mg), K₃PO ₄(326mg) was dissolved in DMF (5mL), and the mixture was replaced with nitrogen three times, and the temperature was raised to 110 ℃ to react for 2 hours. After completion of the reaction, the reaction mixture was diluted with ethyl acetate (100mL), the organic phase was washed with water (60mL) and saturated brine (60mL) in this order, dried over anhydrous sodium sulfate, concentrated and purified by column chromatography (PE: EA: 100:0-70:30) to give 215mg of compound 4-4.

LC-MS[M+H] ⁺：499。

And 5: synthesis of Compounds 4-5

To a 100mL single-necked flask was added 4-4(120mg), Compound M-12(138mg), K₃PO ₄(356mg), CuI (46mg) and DMSO (3mL) were purged with nitrogen three times, and the reaction was stirred at 120 ℃ for 3 hours. After the reaction was completed, the reaction solution was filtered, the filter cake was washed with 3mL of DMSO, and the filtrate was used directly in the next step.

LC-MS[M+H ⁺]：534。

Step 6: synthesis of Compound 4

DCM (12mL), NH was added to the filtrate from step 5 under nitrogen₄Cl (445mg) and DIEA (2.17g), the reaction was cooled to 0 ℃ and HATU (1.27g) was added thereto in portions under ice-bath, followed by stirring at 0 ℃ for 20 min. After the reaction, the reaction mixture was diluted with DCM (50mL), and the organic phase was washed with water (40mL) and saturated brine (40mL), dried over anhydrous sodium sulfate, and concentrated to give the crude product. The crude product was purified by column chromatography (PE: EA 100:0-0:100) to give 89mg of compound 4.

LC-MS[M+H] ⁺：533。

¹H NMR(500MHz,DMSO-d ₆)δ8.08(d,J＝8.9Hz,1H),7.45-7.41(m,3H),7.38-7.35(m,2H),7.28(s,1H),7.06(s,1H),6.34(d,J＝8.9Hz,1H),6.04(s,1H),4.76(s,1H),4.40-4.37(m,4H),3.95(d,J＝8.8Hz,1H),3.60-3.52(m,1H),3.24(q,J＝8.5,7.7Hz,1H),2.75(s,1H),2.26–2.14(m,1H),2.00-1.93(m,3H),1.22(d,J＝7.1Hz,3H),0.88(d,J＝6.8Hz,3H).

Compound 30 and compound 31 can be prepared using a resolution procedure similar to that of step 7 of example 2.

Example 5(2S) -1- (2- (5-cyclopropyl-3-methyl-2, 4-dioxoimidazolidin-1-yl) -5, 6-dihydrobenzo [ f]Imidazo [1,2-d][1,4]Oxazazem

Synthesis of (E) -9-yl) pyrrolidine-2-carboxamide (Compound 5)

Compound 5 was obtained by substituting compound 1-1 with compound 5-0 and p-fluoroaniline with methylamine hydrochloride, using a preparation method similar to that of example 4.

LC-MS[M+H] ⁺：451。

Example 6(2S) -1- (2- (3-cyclobutyl-5-isopropyl-2, 4-dioxoimidazolidin-1-yl) -5, 6-dihydrobenzo [ f]Imidazo [1,2-d ] s][1,4]Oxazazem

Synthesis of (E) -9-yl) pyrrolidine-2-carboxamide (Compound 6)

Compound 6 was obtained by replacing para-fluoroaniline with cyclobutylamine using a preparation method similar to that of example 4.

LC-MS[M+H] ⁺：493。

¹H NMR(500MHz,DMSO-d6)δ8.04(d,J＝9Hz,1H),7.41(s,1H),7.25(s,1H),7.05(s,1H),6.32(d,J＝9Hz,1H),6.03(s,1H),4.52–4.48(m,1H),4.37–4.35(m,4H), 3.94(d,J＝8.5Hz,1H),3.55(t,J＝7Hz,1H),3.23(q,J＝7.2Hz,1H),2.80-2.65(m,3H),2.14–2.12(m,3H),1.96-1.94(m,3H),1.79-1.71(m,3H),1.15(d,J＝7Hz,3H)0.74(d,J＝6.5Hz,3H)。

Example 7(2S) -1- (2- (3-Ethyl-5-isopropyl-2, 4-dioxoimidazolidin-1-yl) -5, 6-dihydrobenzo [ f]Imidazo [1,2-d ] s][1,4]Oxazazem

Synthesis of (E) -9-yl) pyrrolidine-2-carboxamide (Compound 7)

Compound 7 was obtained by replacing compound 3-1 with compound 7-1 and using a preparation method similar to that of example 3. LC-MS [ M + H ]] ⁺：467。

The compounds of the examples of table 1 were prepared in analogy to the examples 1-7, via different reaction starting materials and suitable reagents.

TABLE 1

All of the racemic compounds in table 1 can be prepared synthetically using the corresponding chiral starting materials to give the corresponding enantiomers, or the enantiomers can be separated on chiral columns essentially as described in example 2, step 7.

Comparative example

TABLE 2

By referring to the preparation method of example 102 in WO2017001658, the corresponding starting materials, intermediates and appropriate reagents can be used to obtain the compounds of comparative example 1 (example 102 in WO 2017001658) and comparative example 2 in table 2; the preparation of the compound of comparative example 3 is as follows.

Preparation of comparative example 3

Step 1: synthesis of Compound D3-2

Compound D3-1(2000g) and oxalyl chloride (2019g) were dissolved in dichloromethane (8L), and DMF (5mL) was slowly added dropwise to the reaction system, followed by refluxing for 6 hours. The reaction was concentrated to give 2245g of a suspension containing a yellow solid, which was used directly in the next reaction.

Step 2: synthesis of Compound D3-3

4-methoxy-3-buten-2-one (642g) was dissolved in anhydrous THF (16L) and 6.42L of a solution of LiHMDS (1mol/L) dissolved in THF was added dropwise to the reaction system at-78 ℃. Stirring at-78 deg.C for 2 hr, slowly adding dropwise solution of suspension obtained in step 1 dissolved in anhydrous THF (1L) into the system, stirring at-78 deg.C for 1-2 hr, heating to room temperature, and stirring for 16 hr to obtain reaction solution for further reaction.

LC-MS[M+H] ⁺：239。

And step 3: synthesis of Compound D3-4

The reaction solution obtained in step 2 was quenched by the addition of water (500mL) under ice-water bath conditions, followed by the addition of trifluoroacetic acid (50mL) and stirring was continued at room temperature for 3 hours. After the reaction was completed, the system was concentrated and extracted with EA. The organic phase was washed with brine, anhydrous Na₂SO ₄Drying, concentrating, purifying by column chromatography (Hex/EA 100:1-10:1) to obtain brown solid, washing the solid with a mixed solution of HEX and EA (volume ratio 50:1), suction-filtering, collecting the filtrate, and concentrating to obtain 395g of compound D3-4.

LC-MS[M+H] ⁺：207。

¹H NMR(MeOD-d6):1.59(s,6H),6.39-6.41(m,1H),6.53-6.54(m,1H),8.12-8.14(m,1H)。

And 4, step 4: synthesis of Compound D3-5

Compound D3-4(395g) was added to 2L of aqueous ammonia (30%) and the reaction was stirred at reflux for 2 hours. The reaction solution was cooled and concentrated to give 343.00g of Compound D3-5, which was used directly in the next step.

LC-MS[M+H] ⁺：206。

And 5: synthesis of Compound D3-6

A mixture of compound D3-5(343g) and tribromooxyphosphorus (966.68g) was heated and stirred at 120 ℃ for 1 hour. The hot reaction mixture was poured into ice water, sodium bicarbonate was added, the PH was adjusted to neutral, extracted with EA, the organic phase was dried and concentrated, and purified by column chromatography (Hex/EA 100:1) to give 305g of compound D3-6.

LC-MS[M+H] ⁺：269。

¹H NMR(MeOD-d6):1.59(s,6H),7.52-7.54(m,1H),7.78(s,1H),8.41-8.42(m,1H)。

Step 6: synthesis of Compound D3-7

The pinacol ester diboron (710.45mg), compound D3-6(500mg), potassium acetate (1.88g), and [ PdCl [ ([ PdCl ]) were added to a single vial₂(dppf)]CH ₂Cl ₂(152.32mg) and dioxane (20mL) were reacted in an oil bath at 90 ℃ for 4 hours under nitrogen protection, the reaction solution was concentrated, and the reaction solution was purified by column chromatography (Hex/EA: 3:1) to give 450mg of compound D3-7.

LC-MS[M+H] ⁺：316。

And 7: synthesis of Compound D3-8

Adding [ PdCl ] into a single-mouth bottle₂(dppf)]CH ₂Cl ₂(233.22mg), Potassium carbonate (394.70mg), Compound D3-7(450mg), Compound M-5(586.25mg), dioxane (3mL) and H₂O (0.5mL), under nitrogen, was refluxed for 15 hours in an oil bath at 70 ℃, and the reaction solution was concentrated and purified by column chromatography (PE: EA 50:50) to obtain 130mg of compound D3-8.

LC-MS[M+H] ⁺：452。

And 8: synthesis of Compound D3-9

Compound D3-9 was obtained according to the procedure of step 5 of example 2.

LC-MS[M+H] ⁺：487。

And step 9: synthesis of comparative example 3

The compound of comparative example 3 was obtained by the method of step 6 of reference example 2.

LC-MS[M+H] ⁺：486。

Pharmacological test

The following experiments show that preferred compounds of the invention are effective in inhibiting the activity of PI3K alpha kinase in vitro. The anti-PI 3K alpha mutant tumor cell proliferation activity and the pharmacokinetic experiment result of the preferred compound are superior to those of the control example, and the compound has obvious progress.

Example A: kinase assay

PI3K alpha, PI3K beta and PI3K gamma kinase and its substrate ATP, PIP2:3PS are subjected to enzymological reaction, and the amount of products is detected by using ADP-Glo reagent and a luminescence method so as to reflect the enzymological activities of PI3K alpha, PI3K beta and PI3K gamma (the final concentration of ATP is 10 mu M). Some compounds of the invention were tested for inhibitory activity against PI3K α, PI3K β, and PI3K γ kinases using the methods described above.

The detection method comprises the following steps:

reagent: basal kinase buffer (pH 7.5); PI3K alpha, PI3K beta and PI3K gamma enzyme solutions; PIP2:3PS and ATP solution; ADP-Glo kit (containing 10mM MgCl)₂)。

Wherein, the buffer solution components: 50mM Hepes (pH7.2-7.5), 3mM MgCl₂，1mM EGTA,0.03％CHAPS，100mM NaCl，2mM DTT；

Preparing a compound: test compounds were diluted to specific concentrations using 100% DMSO.

The reaction process is as follows: 1) to a 384 reaction plate (6008280, Perkinelmer) was added a solution of PI3K α, PI3K β, and PI3K γ protein, and centrifuged at 1000rpm for 1 minute.

2) To the above enzyme-added 384 reaction plate, the compound to be tested, negative control DMSO or positive control BYL719, was added, centrifuged at 1000rpm for 1 minute, and incubated at 25 ℃ for 15 minutes.

3) To the above 384 reaction plates was added PIP2:3PS & ATP solution, centrifuged at 1000rpm for 1 min and incubated at 25 ℃ for 60 min.

4) Transfer 5. mu.L of ADP-Glo reagent (containing 10mM MgCl)₂) Into 384 reaction plates, centrifuged at 1000rpm for 1 minute, 25Incubate at deg.C for 40 minutes.

5) Transfer 10. mu.L of Detection reagent to 384 reaction plates, centrifuge at 1000rpm for 1 minute, and incubate at 25 ℃ for 40 minutes.

6) The RLU (relative luminescence unit) value was read using an Envision multifunction plate reader. The RLU value was used to characterize the extent of reaction of the enzyme with the substrate and to calculate the IC₅₀The value is obtained.

7) Experimental data processing procedure:

compound inhibition (% inh) — (negative control RLU-test compound RLU)/(negative control RLU-positive control RLU) × 100%

IC of the compound was obtained using the following non-linear fit equation₅₀(median inhibitory concentration):

y-min inhibition + (max inhibition-min inhibition)/(1 +10^ ((LogIC)₅₀-X) slope)); wherein X is the log of the concentration of the compound to be tested and Y is the inhibition (% inh) of the compound to be tested.

The experimental results of some embodiments of the invention are shown in table 3. Wherein A represents IC₅₀The value is less than or equal to 5 nM; b represents IC₅₀The value is 5-20 nM; c represents IC₅₀The value is 300-600 nM; d represents IC₅₀Value of>600nM。

TABLE 3

Note: "/" indicates not tested.

As can be seen from Table 3, the compound provided by the invention has better PI3K alpha kinase inhibition activity and better PI3K beta and PI3K gamma kinase subtype selectivity, and can avoid potential side effects caused by multi-target inhibition.

Example B: cell proliferation assay

The method comprises the following steps: the CellTiter Glo assay method was used to observe the growth inhibitory effect of some of the compounds of the present invention on MCF-7 and HGC27, human tumor cells cultured in vitro.

The detection method comprises the following steps: MCF-7 cells are suspended in a DMEM medium to form a cell suspension, and the cell concentration is adjusted to 25000 cells/mL; HGC27 cells were suspended in RPMI-1640 medium to form a cell suspension, and the cell concentration was adjusted to 5000 cells/mL. Add 100. mu.L of cell suspension to 96-well plate and place CO₂The incubator was overnight. Compounds to be tested were dissolved in DMSO and diluted in 3-fold gradients to give a total of 10 concentrations. 10 concentrations of test compound or DMSO negative control, respectively, were transferred to wells containing 100. mu.L of medium at 37 ℃ with 5% CO₂Incubation under conditions, HGC27 cells were incubated for 96 hours, and MCF-7 cells were incubated for 120 hours. Then, 100. mu.L of CellTiter-Glo reagent was added to the above 96-well plate, and the plate was incubated at room temperature for 10 minutes to stabilize the luminescence signal. RLU (relative luminescence unit) values were recorded using a VICTOR TM X5 instrument, followed by IC calculation₅₀The value is obtained.

Compound inhibition (% inh) — 100% - (test compound RLU-placebo RLU)/(negative control RLU-placebo RLU) — 100%

Negative control: DMSO wells;

blank control: blank medium wells, no compound and no cells;

the IC of the compound was obtained using the following non-linear fit equation₅₀(median inhibitory concentration):

y-min inhibition + (max inhibition-min inhibition)/(1 +10^ ((LogIC)₅₀-X) slope)); wherein X is the log of the concentration of the compound to be tested; y-inhibition (% inh) of the test compound.

The experimental data are shown in tables 4 and 5.

Table 4 example compounds versus MCF cell IC₅₀The result of the detection

Examples	Compound pair MCF cell IC 50 (MuM)
Comparative example 1	0.444
Comparative example 2	0.549
Comparative example 3	0.519
Example 1	0.176
Example 2	0.070
Example 5	0.373
Example 9	0.142
Example 23	0.074
Example 28	0.468
Example 32	0.107
Examples33	0.047

TABLE 5 example Compounds for HGC-27 cell IC₅₀The result of the detection

Examples	Compound pair HGC-27 cell IC 50 (mu M)
Comparative example 1	1.579
Comparative example 3	2.067
Example 2	0.361
Example 5	4.071
Example 28	3.921
Example 32	0.415
Example 33	0.267

As can be seen from the above table, the compounds provided in the present invention have better cell proliferation inhibitory activity on the cell line with PI3K α point mutation than the control compound, and have better anti-tumor effect at the same concentration. Therefore, the compound provided by the invention is expected to be a PI3K alpha kinase inhibitor with better anti-tumor effect.

Example C: pharmacokinetic testing

The detection method comprises the following steps: male SD rats 42, body weight: 150- & ltSUB & gt 300 g. Groups were randomized into 7 groups of 6 rats. Of 6 rats per group, 3 were given a single intravenous injection of 2mg/mL of the example compound and another 3 were given a single gavage of 10mg/mL of the example compound, blood was collected at the indicated time points via the orbital venous plexus, plasma was isolated and stored in a freezer at-80 ℃ until use.

After the protein is precipitated by acetonitrile, the supernatant is extracted and mixed with water at a ratio of 1:1, 10 mu L of the mixture is taken to be detected by LC-MS/MS, and the average value is calculated, wherein the experimental data are shown in Table 6.

TABLE 6 pharmacokinetic test results for the compounds of the examples

According to relevant statistics (Kola I, Landis J. nat Rev Drug Discov.2004Aug; 3(8):711-5.), in the early 90 s of the last century, about 40% of the reasons for the failure of clinical development of Drug candidates were due to poor PK/bioavailability, which shows that PK/bioavailability plays a very crucial role in the success or failure of clinical development of Drug candidates.

As can be seen from the above table, the compounds provided by the present invention have unexpectedly higher oral exposure and at the same time lower clearance in vivo than the compounds of the control examples; can have higher drug concentration in the body circulation system under the same dosage. On the premise of equivalent anti-tumor effect, the compound of the invention has lower administration dosage, thereby reducing possible toxic reaction and safety risk probability and effectively increasing the druggability of the compound.

Claims

A compound of formula (I) or a stereoisomer, geometric isomer or tautomer thereof, or a pharmaceutically acceptable salt, solvate, chelate, non-covalent complex or prodrug thereof,

wherein,

x is selected from O or S;

R ₁selected from H, CN, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-6Cycloalkyl radical, C_3-6Heterocyclic group, C_6-8Aryl radical, C_5-8Heteroaryl, OR_aor-NR_aR _b(ii) a Said C is_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-6Cycloalkyl radical, C_3-6Heterocycloalkyl radical, C_6-8Aryl and C_5-8Heteroaryl may optionally be substituted by 1 OR more groups selected from halogen, CN, OR_aOxo, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-6Cycloalkyl or C_3-6Heterocyclyl is substituted with a substituent;

R ₂selected from H, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-6Cycloalkyl radical, C_3-6Heterocyclic group, C_6-8Aryl radical, C_5-8A heteroaryl group; said C is_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-6Cycloalkyl radical, C_3-6Heterocyclic group, C_6-8Aryl and C_5-8Heteroaryl groups may optionally be substituted by 1 or moreEach selected from halogen, CN, -OH, -NO₂、C _1-6Alkyl radical, C_1-6Haloalkyl, C_2- ₆Alkenyl radical, C_2-6Haloalkenyl, C_2-6Alkynyl, C_2-6Halogenated alkynyl, C_3-6Cycloalkyl radical, C_3-6Halogenocycloalkyl, C_3-6Heterocyclic group, C_3-6Halogenated heterocyclic group, C_6-8Aryl radical, C_6-8Halogenated aryl, C_5-8Heteroaryl group, C_5-8Haloheteroaryl, oxo, -OR_a、-NR _aR _b、-C(O)R _a、-C(O)O R _a、-C(O)NR _aR _b、-S(O)R _aor-S (O)₂R _aSubstituted with the substituent(s);

R ₃selected from H, halogen, CN, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, -OR_aor-NR_aR _b(ii) a Said C is_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl may optionally be substituted by 1 OR more substituents selected from halogen, CN, -OR_a、-NR _aR _b、-C(O)R _a、-C(O)OR _a、-C(O)NR _aR _b、-S(O)R _aor-S (O)₂R _aSubstituted with the substituent(s);

R ₄selected from H, halogen, CN, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, oxo, C_1-6Haloalkyl, C_2-6Haloalkenyl, C_2-6Halogenated alkynyl, C_1-6Alkoxy radical, C_1-6Haloalkoxy, -OR_a、-NR _aR _b、-C(O)R _a、-C(O)OR _a、-C(O)NR _aR _b、-S(O)R _aor-S (O)₂R _a；

R ₅Selected from H, halogen, CN, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Haloalkyl, C_2-6Haloalkenyl, C_2-6Halogenated alkynyl, C_1-6Alkoxy radical, C_1-6Haloalkoxy, -OR_a、-NR _aR _b、-S(O)R _aor-S (O)₂R _a；

R ₆Selected from H, halogen, CN, oxo, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Alkoxy radical, C_3-6Cycloalkyl, C_3-6Heterocyclic group, C_6-8Aryl radical, C_5-8Heteroaryl, -OR_a、-NR _aR _b、-C(O)R _a、-C(O)O R _a、-C(O)NR _aR _b、-S(O)R _aor-S (O)₂R _a(ii) a Said C is_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Alkoxy radical, C_3-6Cycloalkyl radical, C_3-6Heterocyclic group, C_6-8Aryl and C_5-8Heteroaryl may optionally be substituted by 1 or more groups selected from halogen, CN, oxo, -NO₂、C _1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, -OR_a、-NR _aR _b、-C(O)R _a、-C(O)O R _a、-C(O)NR _aR _b、-S(O)R _aor-S (O)₂R _aSubstituted with a group of (a); or,

two R₆Together with the C atom to which they are attached form C_3-6Cycloalkyl or C_3-6A heterocyclic group;

R _aand R_bEach independently selected from H, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Alkoxy radical, C_3-6Cycloalkyl radical, C_3-6Heterocyclic group, C_6-8Aryl radical, C_5-8A heteroaryl group; said C is_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Alkoxy radical, C_3-6Cycloalkyl radical, C_3-6Heterocyclic group, C_6-8Aryl radical, C_5-8Heteroaryl being optionally substituted by halogen, CN, -OH, -NH₂、C _1-6Alkyl radical, C_1-6Alkoxy radical, C_1-6Haloalkyl, C_1-6Substituted by haloalkoxy;

m is selected from 0, 1,2, 3 or 4;

n is selected from 0, 1,2 or 3;

y is selected from 0, 1,2, 3,4,5 or 6.
A compound according to claim 1, or a stereoisomer, geometric isomer, or tautomer thereof, or a pharmaceutically acceptable salt, solvate, chelate, non-covalent complex, or prodrug thereof, wherein R is₁Is C_1-6Alkyl or C_3-6Cycloalkyl radical, said C_1-6Alkyl and C_3-6Cycloalkyl groups may independently be optionally substituted with halogen.
The compound of any one of claims 1-2, or a stereoisomer, geometric isomer, or tautomer thereof, or a pharmaceutically acceptable salt, solvate, chelate, non-covalent complex, or prodrug thereof, wherein R is ₂Selected from H, C_1-6Alkyl radical, C_3-6Cycloalkyl radical, C_3-6Heterocyclic group, C_6-8Aryl or C_5-8A heteroaryl group; said C is_1-6Alkyl radical, C_3-6Cycloalkyl radical, C_3-6Heterocyclic group, C_6-8Aryl and C_5-8Heteroaryl can be optionally substituted with 1 or more halogens, -CN, -OH, -NR_aR _b、C _1-6Alkyl or C_1-6Haloalkyl; said R is_aAnd R_bEach independently selected from H or C_1-6An alkyl group.
A compound according to any one of claims 1 to 3, or a stereoisomer, geometric isomer or tautomer thereof, or a pharmaceutically acceptable salt, solvate, chelate, non-covalent complex or prodrug thereof, wherein R is₃Selected from H, halogen, CN, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Haloalkyl, C_2-6Haloalkenyl or C_2-6A haloalkynyl group.
A compound according to any one of claims 1 to 4, or a stereoisomer, geometric isomer or tautomer thereof, or a pharmaceutically acceptable salt, solvate, chelate, non-covalent complex or prodrug thereof, wherein R is₆Selected from H, halogen, CN, -NH₂Oxo, -OH, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Alkoxy radical, C_1-6Haloalkyl, C_2-6Haloalkenyl, C_2-6Halogenated alkynyl, C_3-6Cycloalkyl radical, C_3-6Heterocyclic group, C_6-8Aryl or C_5-8A heteroaryl group.
The compound of any one of claims 1 to 5, or a stereoisomer, geometric isomer, or tautomer thereof, or a pharmaceutically acceptable salt, solvate, chelate, non-covalent complex, or prodrug thereof, further represented by formula (ii):
the compound of any one of claims 1 to 6, or a stereoisomer, geometric isomer, or tautomer thereof, or a pharmaceutically acceptable salt, solvate, chelate, non-covalent complex, or prodrug thereof, further represented by formula (iii-1):

wherein, R is₁Is C_1-6Alkyl or C_1-6A haloalkyl group.
The compound of any one of claims 1-6, or a stereoisomer, geometric isomer, or tautomer thereof, or a pharmaceutically acceptable salt, solvate, chelate, non-covalent complex, or prodrug thereof, further represented by formula (iii-2):
a compound according to any one of claims 1 to 8, or a stereoisomer, geometric isomer or tautomer thereof, or a pharmaceutically acceptable salt, solvate, thereof,Chelate, non-covalent complex or prodrug, characterized in that R is₃Selected from H, halogen, C_1-6Alkyl or C_2-6An alkenyl group.
A compound according to any one of claims 1 to 9, or a stereoisomer, geometric isomer, or tautomer thereof, or a pharmaceutically acceptable salt, solvate, chelate, non-covalent complex, or prodrug thereof, wherein R is₄And R₅Are all H.
The compound of any one of claims 1-6, or a stereoisomer, geometric isomer, or tautomer thereof, or a pharmaceutically acceptable salt, solvate, chelate, non-covalent complex, or prodrug thereof, further represented by formula (iv):

wherein:

R ₁is C_1-6Alkyl or C_1-6A haloalkyl group;

R ₂selected from H, C_1-6Alkyl radical, C_3-6Cycloalkyl, C_3-6Heterocyclic group, C_6-8Aryl or C_5-8A heteroaryl group; said C is_1-6Alkyl radical, C_3-6Cycloalkyl radical, C_3-6Heterocyclic group, C_6-8Aryl and C_5-8Heteroaryl can be optionally substituted with 1 or more halogens, -CN, -OH, -NR_aR _b、C _1-6Alkyl radical, C_1-6Haloalkyl, C_1-6Alkoxy or C_1-6Haloalkoxy;

R ₃selected from H, halogen, C_1-6Alkyl or C_2-6An alkenyl group;

R ₆selected from H, halogen, -NH₂Oxo, -OH, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_1-6Haloalkyl, C_1-6Haloalkoxy, C_3-6Cycloalkyl or C_6-8An aryl group;

R _aand R_bEach independently selected from H or C_1-6An alkyl group;

y is selected from 0, 1,2, 3,4,5 or 6.
A compound according to claim 11, or a stereoisomer, geometric isomer, or tautomer thereof, or pharmaceutically acceptable salt, solvate, chelate, non-covalent complex, or prodrug thereof, wherein X is O.
The compound of any one of claims 1-7, or a stereoisomer, geometric isomer, or tautomer thereof, or a pharmaceutically acceptable salt, solvate, chelate, non-covalent complex, or prodrug thereof, further represented by formula (V):
the compound of any one of claims 1-13, or a stereoisomer, geometric isomer, or tautomer thereof, or a pharmaceutically acceptable salt, solvate, chelate, non-covalent complex, or prodrug thereof, wherein R is₂Selected from H, C_1-6Alkyl radical, C_3-6Cycloalkyl radical, C_3-6Heterocyclic group, C₆Aryl or C_5-6A heteroaryl group; said C is_1-6Alkyl radical, C_3-6CycloalkanesBase, C_3-6Heterocyclic group, C₆Aryl and C_5-6Heteroaryl may optionally be substituted by 1 or more halogens, -CN, -OH, -N- (CH)₃) ₂、C _1-6Alkyl or C_1-6Haloalkyl.
The compound of any one of claims 1-14, or a stereoisomer, geometric isomer, or tautomer thereof, or a pharmaceutically acceptable salt, solvate, chelate, non-covalent complex, or prodrug thereof, wherein R is₆Selected from H, halogen, -NH₂Oxo, -OH, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_3-6Cycloalkyl or C₆And (4) an aryl group.
The compound of any one of claims 1-7, or a stereoisomer, geometric isomer, or tautomer thereof, or a pharmaceutically acceptable salt, solvate, chelate, non-covalent complex, or prodrug thereof, further represented by formula (vi):

wherein,

R ₁is selected from C_1-6Alkyl or C_1-6A haloalkyl group;

R ₂selected from H, C_1-6Alkyl radical, C_3-6Cycloalkyl radical, C_3-6Heterocyclic group, C₆Aryl or C_5-6A heteroaryl group; said C is_1-6Alkyl radical, C_3-6Cycloalkyl radical, C_3-6Heterocyclic group, C₆Aryl and C_5-6Heteroaryl may optionally be substituted by 1 or more halogens, -CN, -OH, -N- (CH)₃) ₂、C _1-6Alkyl or C_1-6Haloalkyl.
The compound of any one of claims 1-16, or a stereoisomer, geometric isomer, or tautomer thereof, or a pharmaceutically acceptable salt, solvate, chelate, non-covalent complex, or prodrug thereof, wherein R is₁Is C_1-4Alkyl radical, said R₁Optionally substituted with halogen.
The compound of any one of claims 1-17, or a stereoisomer, geometric isomer, or tautomer thereof, or a pharmaceutically acceptable salt, solvate, chelate, non-covalent complex, or prodrug thereof, wherein R is₁Is selected from-CH (CH)₃) ₂、-C(CH ₃) ₃、-CF ₃or-CHF₂。
The compound of any one of claims 1-18, or a stereoisomer, geometric isomer, or tautomer thereof, or a pharmaceutically acceptable salt, solvate, chelate, non-covalent complex, or prodrug thereof, wherein R is₂Selected from H, C_1-6Alkyl radical, C_3-6Cycloalkyl radical, C_3-6Heterocyclic group, C₆Aryl or C₅-C ₆Heteroaryl of said R₂Optionally substituted with halogen.
The compound of any one of claims 1-19, or a stereoisomer, geometric isomer, or tautomer thereof, or a pharmaceutically acceptable salt, solvate, chelate, non-covalent complex, or prodrug thereof, wherein R is₂Is selected from C_1-6Alkyl radical, C_1-6Haloalkyl, C_3-6Cycloalkyl radical, C _3-6Halocycloalkyl, phenyl or halophenyl.
A compound according to any one of claims 1 to 7, or a stereoisomer, geometric isomer or tautomer thereof, or a pharmaceutically acceptable salt, solvate, chelate, non-covalent complex or prodrug thereof, further represented by formula (vii):

wherein, R is₂Selected from H, C_1-6Alkyl radical, C_3-6Cycloalkyl radical, C_3-6Heterocyclic group, C₆Aryl or C_5-6A heteroaryl group; the R is₂Optionally substituted with halogen.
The compound of any one of claims 1-21, or a stereoisomer, geometric isomer, or tautomer thereof, or a pharmaceutically acceptable salt, solvate, chelate, non-covalent complex, or prodrug thereof, wherein R is₂Is selected from-CH₃、-CH ₂CH ₃、-CH(CH ₃) ₂、-CH ₂CF ₃Cyclopropyl, cyclobutyl, phenyl or pyridyl; the-CH₃、-CH ₂CH ₃、-CH(CH ₃) ₂、-CH ₂CF ₃Cyclopropyl, cyclobutyl, phenyl or pyridyl optionally substituted by halogen.
The compound of any one of claims 1-22, or a stereoisomer, geometric isomer, or tautomer thereof, or a pharmaceutically acceptable salt, solvate, chelate, non-covalent complex, or prodrug thereof, wherein R is ₂Is selected from-CH₃、-CH(CH ₃) ₂Cyclopropyl, phenyl or halo-substituted phenyl.
The compound of claim 1, or a stereoisomer, geometric isomer, or tautomer thereof, or a pharmaceutically acceptable salt, solvate, chelate, non-covalent complex, or prodrug thereof, wherein the compound, or stereoisomer, geometric isomer, or tautomer thereof, is selected from the group consisting of:

1) (2S) -1- (2- (5-isopropyl-3-methyl-2, 4-dioxoimidazolidin-1-yl) -5, 6-dihydrobenzo [ f]Imidazo [1,2-d ] s][1,4]Oxazazem
-9-yl) pyrrolidine-2-carboxamide;

2) (2S) -1- (2- (3-cyclopropyl-5-isopropyl-2, 4-dioxoimidazolidin-1-yl) -5, 6-dihydrobenzo [ f]Imidazole [1,2-d ]][1,4]Oxazazem
-9-yl) pyrrolidine-2-carboxamide;

3) (2S) -1- (2- (5-isopropyl-2, 4-dioxo-3- (2,2, 2-trifluoroethyl) imidazolidin-1-yl) -5, 6-dihydrobenzo [ f]Imidazole [1,2-d ]][1,4]Oxazazem
-9-yl) pyrrolidine-2-carboxamide;

4) (2S) -1- (2- (3- (4-fluorophenyl) -5-isopropyl-2, 4-dioxoimidazolidin-1-yl) -5, 6-dihydrobenzo [ f]Imidazo [1,2-d ] s][1,4]Oxazazepine
-9-yl) pyrrolidine-2-carboxamide;

5)(2S)-1-(2-(5-cyclopropyl-3-methyl-2, 4-dioxoimidazolidin-1-yl) -5, 6-dihydrobenzo [ f]Imidazo [1,2-d ] s][1,4]Oxazazem
-9-yl) pyrrolidine-2-carboxamide;

6) (2S) -1- (2- (3-cyclobutyl-5-isopropyl-2, 4-dioxoimidazolidin-1-yl) -5, 6-dihydrobenzo [ f]Imidazo [1,2-d ] s][1,4]Oxazazem
-9-yl) pyrrolidine-2-carboxamide;

7) (2S) -1- (2- (3-Ethyl-5-isopropyl-2, 4-dioxoimidazolidin-1-yl) -5, 6-dihydrobenzo [ f]Imidazo [1,2-d ] s][1,4]Oxazazem
-9-yl) pyrrolidine-2-carboxamide;

8) (2S) -1- (2- (5-difluoromethyl-3-methyl-2, 4-dioxoimidazolidin-1-yl) -5, 6-dihydrobenzo [ f]Imidazo [1,2-d ] s][1,4]Oxazazem
-9-yl) pyrrolidine-2-carboxamide;

9) (2S) -1- (2- (5-isopropyl-2, 4-dioxo-3-phenylimidazolidin-1-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1,2-d ] s][1,4]Oxazazem
-9-yl) pyrrolidine-2-carboxamide;

10) (S) -1- (2- ((S) -5-isopropyl-2, 4-dioxo-3-phenylimidazolidin-1-yl) -5, 6-dihydrobenzo [ f]Imidazo [1,2-d ] s][1,4]Oxazazem
-9-yl) pyrrolidine-2-carboxamide;

11) (S) -1- (2- ((R) -5-isopropyl-2, 4-dioxo-3-phenylimidazolidin-1-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1,2-d ] s][1,4]Oxazazem
-9-yl) pyrrolidine-2-carboxamide;

12) (2S) -1- (2- (5-isopropyl-2, 4-dioxo-3- (4- (trifluoromethyl) phenyl) imidazolidin-1-yl) -5, 6-dihydrobenzo [ f]Imidazole [1,2-d ]][1,4]Oxazazem
-9-yl) pyrrolidine-2-carboxamide;

13) (2S) -1- (2- (5-isopropyl-2, 4-dioxo-3-propylimidazolidin-1-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1,2-d][1,4]Oxazazem
-9-yl) pyrrolidine-2-carboxamide;

14) (2S) -1- (2- (3-cyclopropyl-5-isopropyl) -2, 4-dioxoimidazolidin-1-yl) -5, 6-dihydrobenzo [ f]Imidazo [1,2-d ] s][1,4]Oxazazem
-9-yl) -2-methylpyrrolidine-2-carboxamide;

15) (2S) -1- (2- (3-cyclopropyl-5-isopropyl) -2, 4-dioxoimidazolidin-1-yl) -5, 6-dihydrobenzo [ f ] imidazo [1,2-d ] [1,4] thiazolin-9-yl) -4, 4-difluoropyrrolidine-2-carboxamide;

16) (2S) -1- (2- (5-isopropyl-3- (1-methyl-1H-1, 2, 4-triazol-5-yl) -2, 4-dioxoimidazolidin-1-yl) -5, 6-dihydrobenzo [ f]Imidazo [1,2-d ] s][1,4]Oxazazepine
-9-yl) pyrrolidine-2-carboxamide;

17) (2S,4S) -4-amino-1- (2- (3-cyclopropyl-5-isopropyl-2, 4-dioxoimidazolidin-1-yl) -5, 6-dihydrobenzo [ f]Imidazole [1,2-d ]][1,4]Oxazazem
-9-yl) pyrrolidine-2-carboxamide;

18) (2S) -1- (2- (3- (2-fluorophenyl) -5-isopropyl-2, 4-dioxoimidazolidin-1-yl) -5, 6-dihydrobenzo [ f]Imidazole [1,2-d ]][1,4]Oxazazem
-9-yl) pyrrolidine-2-carboxamide;

19) (2S) -1- (2- (3- (4-chlorophenyl) -5-isopropyl-2, 4-dioxoimidazolidin-1-yl) -5, 6-dihydrobenzo [ f]Imidazo [1,2-d ] s][1,4]Oxazazem
-9-yl) pyrrolidine-2-carboxamide;

20) (2S) -4- (tert-butoxy) -1- (2- (3-cyclopropyl-5-isopropyl-2, 4-dioxoimidazolidin-1-yl) -5, 6-dihydrobenzo [ f]Imidazole [1,2 ]]-d][1,4]Oxazazem
-9-yl) pyrrolidine-2-carboxamide;

21) (2S) -1- (2- (3-cyclopropyl-5-isopropyl) -2, 4-dioxoimidazolidin-1-yl) -5, 6-dihydrobenzo [ f]Imidazo [1,2-d][1,4]Oxazazem
-9-yl) -4, 4-dimethylpyrrolidine-2-carboxamide;

22) (2S) -1- (2- (3- (2, 2-difluoroethyl) -5-isopropyl-2, 4-dioxoimidazolidin-1-yl) -5, 6-dihydrobenzo [ f]Imidazo [1,2-d ] s][1,4]Oxazazem
-9-yl) pyrrolidine-2-carboxamide;

23) (2S) -1- (2- (3, 5-diisopropyl-2, 4-dioxoimidazolidin-1-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1,2-d][1,4]Oxazazem
-9-yl) pyrrolidine-2-carboxamide;

24) (2S) -1- (2- (3-cyclopropyl-5-isopropyl) -2, 4-dioxoimidazolidin-1-yl) -5, 6-dihydrobenzo [ f]Imidazo [1,2-d ] s][1,4]Oxazazem
-9-yl) -4-phenylpyrrolidine-2-carboxamide;

25) (2S) -1- (2- (3- (3-chloro-5-cyanophenyl) -5-isopropyl-2, 4-dioxoimidazolidin-1-yl) -5, 6-dihydrobenzo [ f ] imidazo [1,2-d ] [1,4] thiazolin-9-yl) pyrrolidine-2-carboxamide;

26) (2S) -1- (2- (3, 5-diisopropyl-2, 4-dioxoimidazolidin-1-yl) -5, 6-dihydrobenzo [ f ] imidazo [1,2-d ] [1,4] thiazolin-9-yl) pyrrolidine-2-carboxamide;

27) (2S) -1- (2- (3-azetidin-3-yl) -5-isopropyl-2, 4-dioxoimidazolidin-1-yl) -5, 6-dihydrobenzo [ f]Imidazo [1,2-d ] s][1,4]Oxazazem
-9-yl) pyrrolidine-2-carboxamide;

28) (2S) -1- (2- (3-methyl-2, 4-dioxoimidazolidin-1-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1,2-d][1,4]Oxazazem
-9-yl) pyrrolidine-2-carboxamide;

29) (2S) -1- (2- (5-tert-butyl-3-methyl-2, 4-dioxoimidazolidin-1-yl) -5, 6-dihydrobenzo [ f]Imidazo [1,2-d ] s][1,4]Oxazazem
-9-yl) pyrrolidine-2-carboxamide;

30) (S) -1- (2- ((R) -3- (4-fluorophenyl) -5-isopropyl-2, 4-dioxoimidazolidin-1-yl) -5, 6-dihydrobenzo [ f]Imidazo [1,2 ] s]-d][1,4]Oxazazem
-9-yl) pyrrolidine-2-carboxamide;

31) (S) -1- (2- ((S) -3- (4-fluorophenyl) -5-isopropyl-2, 4-dioxoimidazolidin-1-yl) -5, 6-dihydrobenzo [ f]Imidazo [1,2 ] s]-d][1,4]Oxazazem
-9-yl) pyrrolidine-2-carboxamide;

32) (2S) -1- (2- ((5R) -3-cyclopropyl-5-isopropyl-2, 4-dioxoimidazolidin-1-yl) -5, 6-dihydrobenzo [ f]Imidazo [1,2-d ] s][1,4]Oxazazem
-9-yl) pyrrolidine-2-carboxamide;

33) (2S) -1- (2- ((5S) -3-cyclopropyl-5-isopropyl-2, 4-dioxoimidazolidin-1-yl) -5, 6-dihydrobenzo [ f]Imidazo [1,2-d ] s][1,4]Oxazazem
-9-yl) pyrrolidine-2-carboxamide;

34) (2S) -1- (2- (3- (2-hydroxyethyl) -5-isopropyl-2, 4-dioxoimidazolidin-1-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1,2-d ] s][1,4]Oxazazepine
-9-yl) pyrrolidine-2-carboxamide;

35) (2S) -1- (2- (3- (2-fluoroethyl) -5-isopropyl-2, 4-dioxoimidazolidin-1-yl) -5, 6-dihydrobenzo [ f]Imidazo [1,2-d ] s][1,4]Oxazazem
-9-yl) pyrrolidine-2-carboxamide;

36) (2S) -1- (2- (3- (2- (dimethylamino) ethyl) -5-) isopropyl-2, 4-dioxoimidazolidin-1-yl) -5, 6-dihydrobenzo [ f]Imidazo [1,2-d ] s][1,4]Oxazazem
-9-yl) pyrrolidine-2-carboxamide;

37) (2S) -1- (2- (3-cyclopropyl-5-isopropyl) -2, 4-dioxoimidazolidin-1-yl) -5, 6-dihydrobenzo [ f ] imidazo [1,2-d ] [1,4] thiazolin-9-yl) pyrrolidine-2-carboxamide;

38) (2S) -1- (2- (3- (6-fluoropyridin-3-yl) -5-isopropyl-2, 4-dioxoimidazolidin-1-yl) -5, 6-dihydrobenzo [ f]Imidazo [1,2-d ] s][1,4]Oxazazem
-9-yl) pyrrolidine-2-carboxamide;

39) (2S) -1- (2- (3- (5-Fluoropyridin-3-Yl) -5-isopropyl-2, 4-dioxoimidazolidin-1-Yl) -5, 6-Dihydrobenzo [ f]Imidazo [1,2 ] s]-d][1,4]Oxazazem
-9-yl) pyrrolidine-2-carboxamide;

40) (2S) -1- (2- (3- (3-cyano-5-fluorophenyl) -5-isopropyl-2, 4-dioxoimidazolidin-1-yl) -5, 6-dihydrobenzo [ f]Imidazo [1,2-d][1,4]Oxazazem
-9-yl) -4-fluoropyrrolidine-2-carboxamide;

41) (2S) -1- (2- (3- (3-Chloropyrimidin-2-yl) -5-isopropyl-2, 4-dioxoimidazolidin-1-yl) -5, 6-dihydrobenzo [ f]Imidazo [1,2-d ] s][1,4]Oxazazem
-9-yl) pyrrolidine-2-carboxamide;

42) (2S) -1- (2- (3-cyclopentyl-5-isopropyl-2, 4-dioxoimidazolidin-1-yl) -5, 6-dihydrobenzo [ f]Imidazole [1,2-d ]][1,4]Oxazazem
-9-yl) pyrrolidine-2-carboxamide;

43) (2S) -1- (2- (3- (cyanomethyl) -5-isopropyl-2, 4-dioxoimidazolidin-1-yl) -5, 6-dihydrobenzo [ f]Imidazo [1,2-d ] s][1,4]Oxazazem
-9-yl) pyrrolidine-2-carboxamide;

44) (2S) -1- (2- (5-isopropyl-3-methyl-2, 4-dioxoimidazolidin-1-yl) -5, 6-dihydrobenzo [ f ] imidazo [1,2-d ] [1,4] thiazolin-9-yl) pyrrolidine-2-carboxamide;

45) (2S) -1- (2- (3- (2, 2-difluoroethyl) -5-isopropyl-2, 4-dioxoimidazolidin-1-yl) -5, 6-dihydrobenzo [ f ] imidazo [1,2-d ] [1,4] thiazolin-9-yl) pyrrolidine-2-carboxamide;

46) (2S) -1- (2- (3-cyclopropyl-5-isopropyl-2, 4-dioxoimidazolidin-1-yl) -3-vinyl-5, 6-dihydrobenzo[f]Imidazo [1,2-d ] s][1,4]Oxazazem
-9-yl) pyrrolidine-2-carboxamide;

47) (2S) -1- (3-chloro-2- (3-cyclopropyl-5-isopropyl-2, 4-dioxoimidazolidin-1-yl) -5, 6-dihydrobenzo [ f]Imidazo [1,2-d ] s][1,4]Oxazazem
-9-yl) pyrrolidine-2-carboxamide;

48) (2S) -1- (2- (3-cyclopropyl-5- (difluoromethyl) -2, 4-dioxoimidazolidin-1-yl) -5, 6-dihydrobenzo [ f ] imidazo [1,2-d ] [1,4] thiazolin-9-yl) pyrrolidine-2-carboxamide;

49) (2S,3S) -1- (2- (3-cyclopropyl-5-isopropyl-2, 4-dioxoimidazolidin-1-yl) -5, 6-dihydrobenzo [ f]Imidazo [1,2-d ] s][1,4]Oxazazem
-9-yl) -3-hydroxypyrrolidine-2-carboxamide;

50) (2S) -1- (2- (3-cyclopropyl-5-isopropyl-2, 4-dioxoimidazolidin-1-yl) -3-methyl-5, 6-dihydrobenzo [ f]Imidazo [1,2-d][1,4]Oxazazem
-9-yl) -4-oxopyrrolidine-2-carboxamide;

51) (2S) -4-cyclohexyl-1- (2- (3-cyclopropyl-5-isopropyl-2, 4-dioxoimidazolidin-1-yl) -5, 6-dihydrobenzo [ f]Imidazo [1,2-d ] s][1,4]Oxazazem
-9-yl) pyrrolidine-2-carboxamide;

52) (2S) -1- (2- (3-cyclopropyl-5-isopropyl-2, 4-dioxoimidazolidin-1-yl) -5, 6-dihydrobenzo [ f ] imidazo [1,2-d ] [1,4] thiazolin-9-yl) -5-oxopyrrolidine-2-carboxamide.
A pharmaceutical composition comprising a therapeutically effective amount of at least one compound of any one of claims 1-24, or a stereoisomer, geometric isomer, or tautomer thereof, or a pharmaceutically acceptable salt, solvate, chelate, non-covalent complex or prodrug thereof, and at least one pharmaceutically acceptable excipient.
The pharmaceutical composition of claim 25, wherein the compound or a stereoisomer, geometric isomer, or tautomer thereof, or a pharmaceutically acceptable salt, solvate, chelate, non-covalent complex or prodrug thereof, and the pharmaceutically acceptable excipient are present in an amount of from about 0.0001 to about 10 weight percent.
Use of a compound of any one of claims 1 to 24, or a stereoisomer, geometric isomer or tautomer thereof, or a pharmaceutically acceptable salt, solvate, chelate, non-covalent complex or prodrug thereof, or a composition of claim 25 or 26, for the manufacture of a medicament.
The use according to claim 27, wherein the medicament is for the treatment, prevention, delay or prevention of the occurrence or progression of cancer or cancer metastasis.
The use according to claim 28, wherein the medicament is for use as a PI3K inhibitor.
The use according to claim 27, wherein the medicament is for the treatment of a PI 3K-mediated disease.
Use according to claim 29 or 30, wherein said PI3K is PI3K α, PI3K β, PI3K δ and/or PI3K γ.
The use of claim 31, wherein said PI3K is PI3K a.
The use of claim 30, wherein the PI 3K-mediated disease is cancer.
The use of claim 33, wherein the cancer is selected from sarcoma, prostate cancer, breast cancer, pancreatic cancer, gastrointestinal cancer, colorectal cancer, thyroid cancer, liver cancer, adrenal cancer, glioma, endometrial cancer, melanoma, kidney cancer, bladder cancer, uterine cancer, vaginal cancer, ovarian cancer, multiple myeloma, esophageal cancer, leukemia, brain cancer, oral and pharyngeal cancer, larynx cancer, lymphoma, basal cell carcinoma, polycythemia vera, primary thrombocythemia.
A method of treating and/or preventing a patient having a PI 3K-mediated disease, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of any one of claims 1-24 or a pharmaceutical composition of claim 25 or 26.
The method of claim 35, wherein the PI3K comprises PI3K a, PI3K β, PI3K δ, and/or PI3K γ.
The method of claim 35, wherein the PI3K is PI3K a.
The method of any one of claims 35-37, wherein the PI 3K-mediated disease is cancer.
The method of claim 38, wherein the cancer is sarcoma, prostate cancer, breast cancer, pancreatic cancer, gastrointestinal cancer, colorectal cancer, thyroid cancer, liver cancer, adrenal cancer, glioma, endometrial cancer, melanoma, kidney cancer, bladder cancer, uterine cancer, vaginal cancer, ovarian cancer, multiple myeloma, esophageal cancer, leukemia, brain cancer, oral and pharyngeal cancer, larynx cancer, lymphoma, basal cell carcinoma, polycythemia vera, primary thrombocythemia.
A method of treating cancer comprising administering to a subject a therapeutically effective amount of a compound of any one of claims 1-24 or a pharmaceutical composition of claim 25 or 26, wherein the cancer is sarcoma, prostate cancer, breast cancer, pancreatic cancer, gastrointestinal cancer, colorectal cancer, thyroid cancer, liver cancer, adrenal cancer, glioma, endometrial cancer, melanoma, kidney cancer, bladder cancer, uterine cancer, vaginal cancer, ovarian cancer, multiple myeloma, esophageal cancer, leukemia, brain cancer, oral and pharyngeal cancer, laryngeal cancer, lymphoma, basal cell carcinoma, polycythemia vera, essential thrombocythemia.
The method of claim 40, wherein the subject is a human.